The role of histone H3 leucine 126 in fine-tuning the copper reductase activity of nucleosomes.

The copper reductase activity of histone H3 suggests undiscovered characteristics within the protein. Here, we investigated the function of leucine 126 (H3L126), which occupies an axial position relative to the copper binding. Typically found as methionine or leucine in copper-binding proteins, the axial ligand influences the reduction potential of the bound ion, modulating its tendency to accept or yield electrons. We found that mutation of H3L126 to methionine (H3L126M) enhanced the enzymatic activity of native yeast nucleosomes in vitro and increased intracellular levels of Cu1+, leading to improved copper-dependent activities including mitochondrial respiration and growth in oxidative media with low copper. Conversely, H3L126 to histidine (H3L126H) mutation decreased nucleosome's enzymatic activity and adversely affected copper-dependent activities in vivo. Our findings demonstrate that H3L126 fine-tunes the copper reductase activity of nucleosomes and highlights the utility of nucleosome enzymatic activity as a novel paradigm to uncover previously unnoticed features of histones.

Natural products and the balancing act of autophagy-dependent/independent ferroptosis in cancer therapy.

The control of biological cell death is essential for the body's appropriate growth. The resistance of cells to the apoptotic process presents a new difficulty in the treatment of cancer. To combat cancer cells, researchers are working to find new apoptotic pathways and components to activate. One of the processes of regulated cell death (RCD) is referred to as ferroptosis marked by a decline in the activity of lipid glutathione peroxidase 4 (GPX4) after the buildup of reactive oxygen species (ROS). Since lipid peroxidation is a crucial component of ferroptosis and is required for its start, numerous medicines have been studied, particularly for the treatment of cancer. In this context, autophagy is an additional form of RCD that can govern ferroptosis through shared signaling pathways/factors involved in both mechanisms. In this review, we will explore the molecular mechanisms underlying ferroptosis and its association with autophagy, to gain fresh insights into their interplay in cancer advancement, and the potential of natural products for its treatment.

Metabolic sinkholes: Histones as methyl repositories.

Perez and Sarkies uncover histones as methyl group repositories in normal and cancer human cells, shedding light on an intriguing function of histone methylation in optimizing the cellular methylation potential independently of gene regulation.

Zinc is Essential for the Copper Reductase Activity of Yeast Nucleosomes.

The histone H3-H4 tetramer is a copper reductase enzyme, facilitating the production of cuprous (Cu1+) ions for distribution to copper-dependent enzymes. It was, however, unknown if this enzymatic activity occurred within nucleosomes. To investigate this, we obtained native nucleosomes from Saccharomyces cerevisiae using micrococcal nuclease digestion of chromatin in isolated nuclei and ion-exchange chromatographic purification. The purified nucleosomal fragments robustly reduced Cu2+ to Cu1+ ions, with the optimal activity dependent on the presence of zinc ions. Mutation of the histone H3 histidine 113 (H3H113) residue at the active site substantially reduced the enzymatic activity of nucleosomes, underscoring the catalytic role of histone H3. Consistently, limiting zinc ions reduced intracellular Cu1+ levels and compromised growth, phenotypes that were mitigated by genetically enhancing the copper reductase activity of histone H3. These results indicate that yeast nucleosomes possess copper reductase activity, suggesting that the fundamental unit of eukaryotic chromatin is an enzyme complex.

The modulatory effects of two bioflavonoids, quercetin and thymoquinone on the expression levels of DNA damage and repair genes in human breast, lung and prostate cancer cell lines.

BACKGROUND: The recent decade has witnessed the increasing potential of various flavonoids such as quercetin and thymoquinone in inhibiting cancer cells proliferation and growth and their therapeutic effects in various cancers. Therefore, in the current study, we aim to evaluate the expression levels of key factors of DNA damage response in human breast, lung and prostate cancer cell lines in response to treatment with quercetin and thymoquinone. METHODS: MTT assay was applied to assess the effects of quercetin and thymoquinone on the viability of MCF-7, A549, and PC3 cancer cells. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of p53, RAD51, Ku70, XRCC1, and H2AX in treated cells. In addition, the expression rate of 8-hydroxy-deoxyguanosine (8-OH-dG) was assessed by ELISA kit. RESULTS: The quercetin and thymoquinone induce cytotoxicity in breast, lung, and prostate cancer cells effectively; MCF-7 cells were the most sensitive cells to quercetin with an IC50 value of 50 µM and PC3 cells were more sensitive to thymoquinone with an IC50 value of 20 µM. The expression levels of DNA damage markers, H2AX, and 8-OH-dG were significantly increased in all cancer cells treated with quercetin and thymoquinone (p < 0.05). Moreover, both flavonoids significantly decreased the expression levels of DNA repair mediators, RAD51, Ku70, XRCC1, in cell lines. P53 was also increased in MCF-7 and A549 cells. CONCLUSION: We concluded that quercetin and thymoquinone may exert their effects through modulation of DNA damage response, increasing DNA damage, and suppressing DNA repair genes.

DNA repair and damage pathways in mesothelioma development and therapy.

Malignant mesothelioma (MMe) is an aggressive neoplasm that occurs through the transformation of mesothelial cells. Asbestos exposure is the main risk factor for MMe carcinogenesis. Other important etiologies for MMe development include DNA damage, over-activation of survival signaling pathways, and failure of DNA damage response (DDR). In this review article, first, we will describe the most important signaling pathways that contribute to MMe development and their interaction with DDR. Then, the contribution of DDR failure in MMe progression will be discussed. Finally, we will review the latest MMe therapeutic strategies that target the DDR pathway.

Synthesis of biocompatible nanocrystalline cellulose against folate receptors as a novel carrier for targeted delivery of doxorubicin.

We designed amine-functionalized nanocrystalline cellulose grafted folic acid/magnetic nanoparticles (AF-NCC/Fe3O4 NPs) against folate receptors for targeted delivery of doxorubicin (DOX). Toxicity is a major side effect of DOX, damaging vital organs such as the heart, kidney, and liver; for example, it causes dilated cardiomyopathy and hepatotoxicity. Accordingly, we aimed to reduce this adverse effect and increase the targeted delivery of DOX to the right point of cancer cells by using the unique features of cancer cells. The characterizations were approved in each step using Fourier transform infrared (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), zeta potential, and dynamic light scattering (DLS) analysis techniques. Encapsulation efficacy of AF-NCC/Fe3O4 NPs was 99.6%; drug release investigations showed excellent stability in physiological conditions (pH âˆ¼ 7.4) and a high release rate in the low pH condition of cancer environments (pH âˆ¼ 5.0). The hemolysis assay and Masson's trichrome and hematoxylin and eosin (H&E) staining results showed that the nanocarrier was entirely biocompatible. In vitro cell viability study approved that the designed nanocarrier increased the therapeutic effects of DOX on Saos-2 cells. The cellular internalization results displayed a high percentage of uptake within 2 h. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was applied for the evaluation of tumor protein p53 (p53), p21, and Bcl-2-associated X protein (Bax). DOX exerted its effects through DNA damage and oxidative stress that led to p53 upregulation, and p53 inhibited cell cycle progression. This arrest initiated apoptosis and inhibited cell migration. In summary, encapsulating DOX in AF-NCC/Fe3O4 NPs dramatically decreases the toxic effects of this chemotherapeutic agent on vital organs, especially on the heart. This smart nanocarrier increases the delivery of DOX using acid folic on its surface and also enhances the DOX release in the acidic environment of cancer cells. DOX exerts its therapeutic effects by the initiation of apoptosis and inhibition of migration.

The molecular mechanism of nuclear signaling for degradation of cytoplasmic DNA: Importance in DNA damage response and cancer.

This review summarizes and addresses non-coding RNAs (rRNA, tRNA, Vault and Y RNA, snRNA, and miRNA) cytoplasmic decay pathways, the molecules, enzymes, and modifications such as uridylation, which play vital roles in the degradation processes in various eukaryotic organisms. Plus, SIRT1's role in fundamental cellular processes, including autophagy, DNA repair, DNA damage response (DDR), and the molecular mechanisms, is explored. Further, the HuR (an RNA-binding protein) impact on the expression of genes following DNA damage, and the pathways that regulate HuR function, which is through phosphorylation by Chk1/Cdk1 and Chk2, are specified. Finally, the role of DIF1/ Rnr2-Rnr4 in DDR has been discussed.

The cross-talk between signaling pathways, noncoding RNAs and DNA damage response: Emerging players in cancer progression.

The DNA damage response (DDR) pathway's primary purpose is to maintain the genome structure's integrity and stability. A great deal of effort has done to understand the exact molecular mechanisms of non-coding RNAs, such as lncRNA, miRNAs, and circRNAs, in distinct cellular and genomic processes and cancer progression. In this regard, the ncRNAs possible regulatory role in DDR via modulation of key components expression and controlling repair signaling pathway activation is validated. Therefore, in this article, we will discuss the latest developments of ncRNAs contribution in different aspects of DNA repair through regulation of ATM-ATR, P53, and other regulatory signaling pathways.

DNA damage response and breast cancer development: Possible therapeutic applications of ATR, ATM, PARP, BRCA1 inhibition.

Breast cancer is the most common and significant cancers in females regarding the loss of life quality. Similar to other cancers, one of the etiologic factors in breast cancer is DNA damage. A plethora of molecules are responsible for sensing DNA damage and mediating actions which lead to DNA repair, senescence, cell cycle arrest and if damage is unbearable to apoptosis. In each of these, aberrations leading to unrepaired damage was resulted in uncontrolled proliferation and cancer. Another cellular function is autophagy defined as a process eliminating of unnecessary proteins in stress cases involved in pathogenesis of cancer. Knowing their role in cancer, scholars have tried to develop strategies in order to target DDR and autophagy. Further, the interactions of DDR and autophagy plus their regulatory role on each other have been focused simultaneously. The present review study has aimed to illustrate the importance of DDR and autophagy in breast cancer according to the related studies and uncover the relation between DDR and autophagy and its significance in breast cancer therapy.

MicroRNA-26a-5p as a potential predictive factor for determining the effectiveness of trastuzumab therapy in HER-2 positive breast cancer patients.

BACKGROUND: Breast cancer (BC) is known as the most prevalent type of cancer among women. Trastuzumab, as an anticancer drug, has been used broadly in human epidermal growth factor receptor 2 (HER-2) positive (+) BC patients. Moreover, accumulating evidence has demonstrated that microRNAs is involved in the pathogenesis BC. Hence, we aimed to investigate the effect of trastuzumab on the expression levels of microRNA-26a in HER-2 positive BC patients. METHODS: This study was conducted among HER-2 + and HER-2 Negative (-) BC patients. Serum expression of microRNA-26a was detected by real-time PCR. Then, we assessed the correlations of microRNA-26a levels with multiple clinico-pathological characteristics of BC. RESULTS: In HER-2 + patients, the microRNA-26a expression significantly increased after treatment with Docetaxel/Trastuzumab in comparison to before the treatment levels (p.value = 0.01). However, this overexpression in HER-2-patients after treatment with Docetaxel was not significant compared to the levels before the treatment (p.value = 0.14). In addition, the expression of microRNA -26a has significantly increased in HER-2 + patients who were ≤48 years old and premenopausal after the treatment with Docetaxel/Trastuzumab when compared to the levels before the treatment (p.value = 0.039 vs. 0.031, respectively). Furthermore, there was a significant correlation between the expression of microRNA -26a and the tumor size, stage, estrogen receptor (ER) and progesterone receptor (PR) status in the HER-2 + group before and after the treatment (p.value = 0.043, 0.042, 0.049 and 0.034 respectively). CONCLUSIONS: Trastuzumab led to overexpression of microRNA-26a in HER-2 + BC patients. It seems that the detecting microRNA -26a expression levels, during or after the trastuzumab therapy could be a useful biomarker for monitoring the therapeutic response in HER-2 + BC patients. However, further studies on large populations of women with HER-2+ BC are needed to explore this possible novel biomarker, in more detail, within various clinical contexts.

Modulation of telomerase expression and function by miRNAs: Anti-cancer potential.

Telomerase is a nucleoprotein reverse transcriptase that maintains the telomere, a protective structure at the ends of the chromosome, and is active in cancer cells, stem cells, and fetal cells. Telomerase immortalizes cancer cells and induces unlimited cell division by preventing telomere shortening. Immortalized cancer cells have unlimited proliferative potential due to telomerase activity that causes tumorigenesis and malignancy. Therefore, telomerase can be a lucrative anti-cancer target. The regulation of catalytic subunit of telomerase (TERT) determines the extent of telomerase activity. miRNAs, as an endogenous regulator of gene expression, can control telomerase activity by targeting TERT mRNA. miRNAs that have a decreasing effect on TERT translation mediate modulation of telomerase activity in cancer cells by binding to TERT mRNA and regulating TERT translation. In this review, we provide an update on miRNAs that influence telomerase activity by regulation of TERT translation.

CRISPR/Cas9 novel therapeutic road for the treatment of neurodegenerative diseases.

CRISPR (clustered regularly interspaced short palindromic Repeats)/Cas9 is a new genetic editing technology that can be a beneficial method to advance gene therapy. CRISPR technology is a defense system of some bacteria against invading viruses. Genome editing based on the CRISPR/Cas9 system is an efficient and potential technology that can be a viable alternative to traditional methods. This system is a compound of a short guide RNAs (gRNAs) for identifying the target DNA sequence and Cas9 protein as nuclease for breaking and cutting of DNA. In this review, recent advances in the CRISPR/Cas9-mediated genome editing tools are presented as well as their use in gene therapy strategies for the treatment of neurological disorders including Parkinson's disease, Alzheimer's disease, and Huntington's disease.

miRNA-29a reverses P-glycoprotein-mediated drug resistance and inhibits proliferation via up-regulation of PTEN in colon cancer cells.

Colon cancer is a serious malignant type of cancer in the world. Acquisition of multi-drug resistance (MDR) during chemotherapy is still a controversial challenge during cancer treatment. Accordingly, detection of safe and impressive MDR-reversing targets such as microRNAs (miRNAs/miRs) can play critical role in cancer treatment. Here, the functional effects of miR-29a in chemo-resistant colon cancer cells is scrutinized. The effect of doxorubicin (DOX) on cell proliferation after miR-29a transfection has been evaluated using MTT assay in HT29 and HT29/DOX cells. Rhodamine123 (Rh123) assay is used to identify the activity of common drug efflux through membrane transporters P-glycoprotein (P-gp). P-gp and PTEN mRNA/protein expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analyses. Flow cytometry was employed to the investigation of apoptosis. ANOVA followed by Bonferroni's and Sidak's tests were used to compare the data from different groups. Thus, it was shown that miRNA-29a overexpression considerably inhibited the HT29/DOX viability. miR-29a significantly down-regulated P-gp expression and activity in HT29/DOX cells and declined drug resistance through elevation of intracellular DOX. Furthermore, upon miRNA-29a transfection, PTEN expression could be restored in resistant cells. These results have indicated that miR-29a target PTEN ultimately P-gp, which is downstream of PTEN, inhibit drug resistance, proliferation, and apoptosis through PI3K/Akt pathway. As a result, miR-29a overexpression is led to enhance the sensitivity of HT29/DOX cells to DOX-treatment by targeting P-gp. MiR-29a might proffer a novel promising candidate for colon cancer therapeutics during chemotherapy.

Red Cell Distribution Width as a Novel Prognostic Marker in Multiple Clinical Studies.

Red cell distribution width (RDW), which is a quantitative method applied for the measurement of anisocytosis, is the most reliable and inexpensive method for differentiation of iron deficiency anemia and thalassemia trait. An increase in its rate reflects a great heterogeneity in the size of red blood cells (RBCs). Recent studies have shown a significant relationship between RDW and the risk of morbidity and mortality in patients with multiple diseases. A strong association is established between changes in RDW and the risk of adverse outcome in patients with heart failure in multiple studies. In this review, we try to focus on the association and correlation between the increase in RDW and different outcomes of common diseases that may be related to RDW and based on the results of various studies, we are trying to introduce RDW as a diagnostic indicator for these diseases. HOW TO CITE THIS ARTICLE: Yousefi B, Sanaie S, Ghamari AA, Soleimanpour H, Karimian A, Mahmoodpoor A. Red Cell Distribution Width as a Novel Prognostic Marker in Multiple Clinical Studies. Indian J Crit Care Med 2020;24(1):49-54.

Multiple functions of microfluidic platforms: Characterization and applications in tissue engineering and diagnosis of cancer.

Microfluidic system, or lab-on-a-chip, has grown explosively. This system has been used in research for the first time and then entered in the clinical section. Due to economic reasons, this technique has been used for screening of laboratory and clinical indices. The microfluidic system solves some difficulties accompanied by clinical and biological applications. In this review, the interpretation and analysis of some recent developments in microfluidic systems in biomedical applications with more emphasis on tissue engineering and cancer will be discussed. Moreover, we try to discuss the features and functions of microfluidic systems.

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons.

Multidrug resistance (MDR), defined as the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, is an important barrier in treating malignancies. Initially, it was discovered that cellular pumps dependent on ATP were the cause of resistance to chemotherapy, and further studies have found that other mechanisms such as increased metabolism of drugs, decreased drug entry, and defective apoptotic pathways are involved in this process. MDR has been the focus of numerous initiatives and countless studies have been undertaken to better understand MDR and formulate strategies to overcome its effects. The current review highlights various nano-drug delivery systems including polymeric/solid lipid/mesoporous silica/metal nanoparticles, dendrimers, liposomes, micelles, and nanostructured lipid carriers to overcome the mechanism of MDR. Nanoparticles are novel gateways to enhance the therapeutic efficacy of anticancer agents at the target site of action due to their tumor-targeting abilities, which can limit the unwanted systemic effects of chemotherapy agents and also reduce drug resistance. Additionally, other innovative strategies including RNA interference as a biological process used to inhibit or silence specific gene expression, natural products as MDR modulators with little systemic toxic effects, which interfere with the functions of proteins involved in drug efflux, and physical approaches such as combination of conventional drug administration with thermal/ultrasound/photodynamic strategies are also highlighted.

The effects of statins with a high hepatoselectivity rank on the extra-hepatic tissues; New functions for statins.

Statins, as the most common treatment for hyperlipidemia, exert effects beyond their lipid-lowering role which are known as pleiotropic effects. These effects are mainly due to the inhibition of isoprenoids synthesis and consequently blocking prenylation of proteins involved in the cellular signaling pathways regulating cell development, growth, and apoptosis. Statins target cholesterol synthesis in the liver as the major source of cholesterol in the body and so reduce whole-body cholesterol. The reduced level of cholesterol forces other organs to an adaptive homeostatic reaction to increase their cholesterol synthesis capacity, however, this only occurs when statins have unremarkable access to the extra-hepatic tissues. In order to reduce the adverse effects of statin on the skeletal muscle, most recent efforts have been towards formulating new statins with the highest level of hepatoselectivity rank and the least level of access to the extra-hepatic tissues; however, the inaccessibility of statins for the extra-hepatic tissues may induce several biological reactions. In this review, we aim to evaluate the effects of statins on the extra-hepatic tissues when statins have unremarkable access to these tissues.

Critical roles of long noncoding RNAs in breast cancer.

Breast cancer is a major clinical challenge that affects a wide range of the female population and heavily burdens the health system. In the past few decades, attempts have been made to understand the etiology of breast cancer, possible environmental risk factors, and the genetic predispositions, pathogenesis, and molecular aberrations involved in the process. Studies have shown that breast cancer is a heterogeneous entity; each subtype has its specific set of aberrations in different cell signaling pathways, such as Notch, Wnt/ß-catenin, transforming growth factor-ß, and mitogen-activated protein kinase pathways. One novel group of molecules that have been shown to be inducted in the regulation of multiple cell signaling pathways is the long noncoding RNAs (lncRNAs). These molecules have important implications in the regulation of multiple signaling pathways by interacting with various genes, affecting the transcription process, and finally, playing roles in posttranslational control of these genes. There is growing evidence that lncRNAs are involved in the process of breast cancer formation by effecting the aforementioned signaling pathways, and that this involvement can have significant diagnostic and prognostic values in clinical contexts. The present review aims to elicit the significance of lncRNAs in the regulation of cell signaling pathways, and the resulting changes in cell survival, proliferation, and invasion, which are the hallmarks of breast cancer.

Targeting miRNAs by polyphenols: Novel therapeutic strategy for aging.

Regarding the importance of genetic and epigenetic factors in regulation of aging process, different expression pattern of non-coding RNAs in aging could be investigated. Accordingly, micro RNAs (miRNAs) with a wide range of physiological functions as well as a significant footprint in many diseases have been demonstrated to be down or upregulated during the aging process. Therefore, age-associated microRNAs and their targets have potentially detected the accelerated aging and predicted the risks for age-related diseases. Polyphenols as important antioxidants in human dietary observed in fruits and some beverages have beneficial effects on longevity and aging. Considering miRNAs as an interesting mediator in modulating polyphenols' biological effects, targeting miRNAs which is using polyphenols could be a novel strategy for aging.