Association Between NAD(P)H Quinone Oxidoreductase 1 (NQO1) Gene Methylation/Expression and Bleeding Incidence Among an Iranian Population Undergoing Warfarin Therapy.

Increased bleeding tendency is a common and challenging complication of warfarin therapy which results in extensive pharmacogenomic studies in order to develop a personalized dosing approach and minimize the risk of related side effects. Here we aimed to explore the potential role of NQO1 gene expression in warfarin response in a group of Iranian patients. We also evaluated the NQO1 promoter methylation and its association with mRNA expression. A total of 87 patients on warfarin therapy including 34 cases with drug-induced bleeding events and 53 matched controls without bleedings were included in the study. The expression of NQO1 was examined by real-time q-PCR and the methylation status of its promoter region was analyzed using methyQESD technique. There was a significant association between the reduced NQO1 gene expression and susceptibility to bleeding before (OR = 1.92, 95% CI = 1.23-3.00, p = 0.004) and following adjustment for hypertriglyceridemia (OR = 2.22, 95% CI = 1.33-3.69, p = 0.002). Furthermore, a medium negative correlation was observed between NQO1 expression and its promoter methylation (r = - 0.382, p = 0.001). The lower expression of NQO1 which partly arises from increased methylation of promoter region, may predispose warfarin treated patients to bleeding events.

Combination of losartan with pirfenidone: a protective anti-fibrotic against pulmonary fibrosis induced by bleomycin in rats.

Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-ß (TGF-ß1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improved by PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis.

Evaluating the protective effect of metformin against diclofenac-induced oxidative stress and hepatic damage: In vitro and in vivo studies.

Diclofenac (DIC) is one of the most commonly prescribed non-steroidal anti-inflammatory drugs and has been shown to cause oxidative stress and liver injury. The current study investigated protective effects of metformin against DIC-induced hepatic toxicity in both in vitro and in vivo models. For the in vitro study, HepG2 cells were exposed to DIC in the presence or absence of metformin. The effect of metformin on cell viability was evaluated by MTT assay. Oxidative stress parameters (malondialdehyde (MDA), total thiol molecules (TTM), and total antioxidant capacity (TAC)) were assessed. For the in vivo study, thirty-six male Wistar rats were randomly divided into 6 groups. These groups were normal saline, metformin (200 mg/kg), DIC (50 mg/kg/day), DIC + metformin (50, 100, and 200 mg/kg/day). Histopathological studies and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), albumin, direct and total bilirubin were measured. Also, oxidative stress parameters were assessed in liver tissue. Furthermore, expression of glutathione peroxidase (GPX)-1, -3, and -4, catalase (CAT), superoxide dismutase (SOD)-1, and -3 was examined using the real-time PCR method in hepatic tissue. In the in vitro study, metformin significantly prevented DIC-induced loss in cell viability in HepG2 cells. Metformin markedly reduced DIC-induced elevation of MDA levels and increased the TAC and TTM levels. In the in vivo study, metformin significantly prevented DIC-induced changes in hematological and histological markers. Administration of metformin significantly improved oxidative stress parameters in liver tissue. In addition, metformin increased the expression of antioxidant enzymes. Our results suggest that metformin exerts a significant protective effect against DIC-induced hepatic toxicity.

Losartan enhances the suppressive effect of pirfenidone on the bleomycin-induced epithelial-mesenchymal transition and oxidative stress in A549 cell line.

Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Despite the promising anti-fibrotic effect, the toleration of pirfenidone (PFD) by the patients in full dose is low. Combination therapy is a method for enhancing the therapeutic efficiency of PFD and decreasing its dose. Therefore, the present study evaluated the effect of a combination of losartan (LOS) and PFD on oxidative stress parameters and the epithelial-mesenchymal transition (EMT) process induced by bleomycin (BLM) in human lung adenocarcinoma A549 cells. Materials and Methods: The non-toxic concentrations of BLM, LOS, and PFD were assessed by the MTT assay. Malondialdehyde (MDA) and anti-oxidant enzyme activity including catalase (CAT) and superoxide dismutase (SOD) were assessed after co-treatment. Migration and western blot assays were used to evaluate EMT in BLM-exposed A549 after single or combined treatments. Results: The combination treatment exhibited a remarkable decrease in cellular migration compared with both single and BLM-exposed groups. Furthermore, the combination treatment significantly improved cellular anti-oxidant markers compared with the BLM-treated group. Moreover, combined therapy markedly increased epithelial markers while decreasing mesenchymal markers. Conclusion: This in vitro study revealed that the combination of PFD with LOS might be more protective in pulmonary fibrosis (PF) than single therapy because of its greater efficacy in regulating the EMT process and oxidative stress. The current results might offer a promising therapeutic strategy for the future clinical therapy of lung fibrosis.

Ameliorating Effect of Standardized Extract From Textured Soy Protein (Glycine max L.) on Memory Deficit and Learning Insufficiency in Scopolamine-induced Amnesia.

Introduction: Textured soy protein (TSP) and nuts are two processed forms of soybean (Glycine max L.) that are widely consumed for nutritional purposes in Iran. Recently, we have reported the antioxidant and anticholinesterase effects of raw soybean (RS) attributed to isoflavones, such as genistein. In this work, we aimed to compare in vitro antioxidant and anticholinesterase effects of TSP, nuts, and RS to select the most effective one for learning capacity and spatial memory studies. Methods: Genistein content was determined using high-performance thin layer chromatography (HPTLC), while diphenylpicrylhydrazil (DPPH) radical scavenging and ferric reducing antioxidant power (FRAP) were used to study antioxidant evaluation and Ellman's colorimetric method was used to measure anticholinesterase. TSP extract (TSPE) was administered to male rats (100 mg/kg, 200 mg/kg and 400 mg/kg, intraperitoneally [i.p] for 7 days) before scopolamine injection (1 mg/kg). Learning capacity and spatial memory were evaluated using passive avoidance test (PAT) and Morris water maze (MWM) methods compared to physostigmine and piracetam. Results: The greatest antioxidant and anticholinesterase effect was observed for TSPE, which significantly prolonged initially latency in PTA (P<0.05) and improved all indicators in the MWM test at 200 mg/kg. Conclusion: The memory-improving effect of TSPE may be due to its antioxidant and anticholinesterase effect as well as neuroprotective effects of its isoflavones. Highlights: Different samples (nuts-raw soybeans-TSP) prepared from soybeans.All samples exhibited antioxidant and anti-cholinesterase effects in vitro studies.TSP showed the most biological activity and the greatest genistein content.TSP significantly improved memory and learning indicators at 200 mg/kg.These effects are attributed to its antioxidant and anticholinesterase activity.Plant isoflavones have neuroprotective effects. Plain Language Summary: Alzheimer's disease (AD), is one of the problems of the elderly society, which has a lot of emotional and financial costs. AD is a type of progressive brain disease in which neurons are destroyed and memory is lost. This disease currently has no definitive treatment and the only way is to prevent the disease from spreading. Much research has been devoted to finding suitable and effective treatments for AD. Many food and herbal medicines have shown to be effective in controlling this disease. Soybean is a plant that is widely used as food and snacks in Iran in different ways. In this study, we prepared three preparation from soya beans which have been widely used by Iranian people including raw soya, nut (roasted form) and textured soy protein (TSP). The effect of these preparations have been studied on memory and learning in amnestic rats through different pharmacological studies. The results indicated that TSP due to antioxidant and anticholinesterase activity significantly can augment memory enhancing and learning ability Alzheimer's disease (AD), is one of the problems of the elderly society, which has a lot of emotional and financial costs. AD is a type of progressive brain disease in which neurons are destroyed and memory is lost. This disease currently has no definitive treatment and the only way is to prevent the disease from spreading. Much research has been devoted to finding suitable and effective treatments for AD. Many food and herbal medicines have shown to be effective in controlling this disease. Soybean is a plant that is widely used as food and snacks in Iran in different ways. In this study, we prepared three preparation from soya beans which have been widely used by Iranian people including raw soya, nut (roasted form) and textured soy protein (TSP). The effect of these preparations have been studied on memory and learning in amnestic rats through different pharmacological studies. The results indicated that TSP due to antioxidant and anticholinesterase activity significantly can augment memory enhancing and learning ability. TSP also contains some phytochemicals such as phytoestrogens which have shown neuroprotective activity in different studies.

Cytotoxicity of mancozeb on Sertoli-germ cell co-culture system: Role of MAPK signaling pathway.

Mancozeb (MZB) is a worldwide fungicide for the management of fungal diseases in agriculture and industrial contexts. Human exposure occurs by consuming contaminated plants, drinking water, and occupational exposure. There are reports on MZB's reprotoxicity such as testicular structure damage, sperm abnormalities, and decrease in sperm parameters (number, viability, and motility), but its molecular mechanism on apoptosis in testis remains limited. To investigate the molecular mechanisms involved in male reprotoxicity induced by MZB, we used primary cultures of mouse Sertoli-germ cells. Cells were exposed to MZB (1.5, 2.5, and 3.5 µM) for 3 h to evaluate viability by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, reactive oxygen species (ROS) generation, and oxidative stress parameters (lipid peroxidation). Cell death and mitogen-activated protein kinase (MAPK) signaling were measured in these cells using flow cytometry and western blotting. In addition, some groups were exposed to N-acetylcysteine (NAC, 5 mM) in the form of co-treatment with MZB. Mancozeb reduced viability and increased the level of intracellular ROS, p38 and c-Jun N-terminal kinases (JNK) MAPK proteins phosphorylation, and apoptotic cell death, which could be blocked by NAC as an inhibitor of oxidative stress. The present study indicated for the first time the toxic manifestations of MZB on the Sertoli-germ cell co-culture. Redox imbalance and p38 and JNK signaling pathway activation might play critical roles in MZB-induced apoptosis in the male reproductive system.

Small nucleolar RNA host genes promoting epithelial-mesenchymal transition lead cancer progression and metastasis.

The small nucleolar RNA host genes (SNHGs) belong to the long non-coding RNAs and are reported to be able to influence all three levels of cellular information-bearing molecules, that is, DNA, RNA, and proteins, resulting in the generation of complex phenomena. As the host genes of the small nucleolar RNAs (snoRNAs), they are commonly localized in the nucleolus, where they exert multiple regulatory functions orchestrating cellular homeostasis and differentiation as well as metastasis and chemoresistance. Indeed, worldwide literature has reported their involvement in the epithelial-mesenchymal transition (EMT) of different histotypes of cancer, being able to exploit peculiar features, for example, the possibility to act both in the nucleus and the cytoplasm. Moreover, SNHGs regulation is a fundamental topic to better understand their role in tumor progression albeit such mechanism is still debated. Here, we reviewed the biological functions of SNHGs in particular in the EMT process and discussed the perspectives for new cancer therapies.

The effects of methanolic extract of Glycyrrhiza glabra on the prevention and treatment of bleomycin-induced pulmonary fibrosis in rat: experimental study.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by dyspnea and progressive loss of lung function. In this study, the preventive and therapeutic effects of methanolic extract of Glycyrrhiza glabra on pulmonary fibrosis were investigated. Pulmonary fibrosis was induced by administration of bleomycin (BLM) into the left lung of rats. Methyl-prednisolone (M-pred, 4 mg/kg) and methanolic extract of G. glabra (500 mg/kg) were injected intraperitoneally from the 1st to 14th days in the preventive group and from the 14th to 28th days in the therapeutic group once every day. Pulmonary inflammatory and fibrotic indices were evaluated by hematoxylin and eosin (H&E) and Masson's trichrome, respectively. The level of hydroxyproline as an index of pulmonary fibrosis and malondialdehyde (MDA) as an oxidative stress biomarker and catalase were measured by the related ELISA Kits. Pulmonary inflammatory and fibrotic indices in the G. glabra and M-pred groups significantly reduced compared with BLM group. G. glabra decreased the level of hydroxyproline in pulmonary tissue similar to M-pred. MDA reduced in G. glabra and M-pred groups compared with BLM group. The activity of catalase increased in the G. glabra preventive group. According to the results, G. glabra prevented and treated pulmonary fibrosis and inflammation in rats. Therefore, G. glabra may be suggested for the prevention and treatment of pulmonary fibrosis and inflammation.

Cytotoxicity evaluation of curcumin-loaded affibody-decorated liposomes against breast cancerous cell lines.

Curcumin is known as an effective anticancer herbal medicine but unfortunately, its bioavailability is poor which necessitate efforts for developing more efficient and specific delivery systems. Human epidermal growth factor receptor 2 (HER 2) due to its overexpression in various types of cancers, is demonstrated to be a good candidate as a target for anticancer therapy. In this study, cytotoxicity of curcumin encapsulated in ZHER2:342 Affibody-decorated liposome was investigated against SKBR3 and MCF-7 cancerous cell lines. Curcumin-containing liposomes were prepared from soybeans lecetin and cholesterol by thin-film hydration method. Affibody ZHER2:342 molecules via C-terminal cysteine residue were conjugated covalently to the prepared liposomes. Particle size analysis was performed using atomic force microscopy (AFM) and dynamic light scattering (DLS). Curcumin loading was measured using UV-Vis spectrophotometry and cytotoxic activity of curcumin formulations against cancerous cell lines was investigated by MTT assay. Induction of apoptosis was investigated using flow cytometry through Annexin V staining. Particle analysis showed the formation of spherical liposomes with a mean diameter of about 150 nm. Cytotoxic activity of curcumin was improved by its encapsulation in both liposomes and affibody-decorated liposomes. The Annexin V staining indicated the induction of apoptosis by affibody-decorated liposomes in both MCF-7 and SKBR3 cells. Decoration of curcumin-loaded liposomes with affibody ZHER2:342 may improve curcumin apoptotic function independently of HER2 expression level.

The association between CYBA gene C242T variant and risk of metabolic syndrome.

BACKGROUND: Both inflammation and oxidative stress may contribute to pathogenesis of metabolic syndrome (MetS). The C242T polymorphism (rs4673) in the CYBA gene, as the main components of NAD (P) H oxidase, causes inter-individual variability in the enzyme activity. We aimed to investigate the association between this polymorphism with MetS and its components. METHODS: Two hundred nine patients with MetS and 232 controls were included in this study. MetS was defined based on NCEP ATP-III A criteria with some modifications. The C242T polymorphism within CYBA gene was determined by using PCR-based restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: After applying a multiple logistic regression model with adjusting for potential confounders of MetS including, age, sex, body mass index, hypertension, used medications, and diabetes mellitus, C242T polymorphism was found to be associated with the presence of MetS in men but not in the total population or in women. T allele as compared to C allele was associated with decreased odds of MetS in men (adjusted OR = 0.42, 95% CI = 0.24-0.74; P = .003), but not in women (adjusted OR = 1.03, 95% CI = 0.07-1.61; P = .890), or in the total population (adjusted OR = 0.72, 95% CI = 0.51-1.02; P = .063). CONCLUSION: This study shows that T allele of C242T polymorphism in CYBA gene is protective against MetS in Iranian men but not in women. Further cohort studies with larger sample size in subgroups of men and women are required to confirm such association in other racial or ethnic group.

Where ferroptosis inhibitors and paraquat detoxification mechanisms intersect, exploring possible treatment strategies.

Paraquat (PQ) is a fast-acting and effective herbicide that is used throughout the world to eliminate weeds. Over the past years, PQ was considered one of the most popular poisoning substances for suicide, and PQ poisoning accounts for about one-third of suicides around the world. Poisoning with PQ may cause multiorgan failure, pulmonary fibrosis, and ultimately death. Exposure to PQ results in the accumulation of PQ in the lungs, causing severe damage and, eventually, fibrosis. Until now, no effective antidote has been found to treat poisoning with PQ. In general, the toxicity of PQ is due to the formation of high energy oxygen free radicals and the peroxidation of unsaturated lipids in the cell. Ferroptosis is the result of the loss of glutathione peroxidase 4 (GPX4) activity that transforms iron-dependent lipid hydroperoxides to lipid alcohols, which are inert in the biological environment. Impaired iron metabolism and lipid peroxidation are increasingly known as the driving agents of ferroptosis. The contribution of ferroptosis to the development of cell death during poisoning with PQ has not yet been addressed. There is growing evidence about the relationship between PQ poisoning and ferroptosis. This raises the possibility of using ferroptosis inhibitors for the treatment of PQ poisoning. In this hypothesis-driven review article, we elaborated how ferroptosis inhibitors might circumvent the toxicity induced by PQ and may be potentially useful for the treatment of PQ toxicity.

EMT signaling: potential contribution of CRISPR/Cas gene editing.

Epithelial to mesenchymal transition (EMT) is a complex plastic and reversible cellular process that has critical roles in diverse physiological and pathological phenomena. EMT is involved in embryonic development, organogenesis and tissue repair, as well as in fibrosis, cancer metastasis and drug resistance. In recent years, the ability to edit the genome using the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system has greatly contributed to identify or validate critical genes in pathway signaling. This review delineates the complex EMT networks and discusses recent studies that have used CRISPR/Cas technology to further advance our understanding of the EMT process.

Topoisomerase inhibitors: Pharmacology and emerging nanoscale delivery systems.

Topoisomerase enzymes have shown unique roles in replication and transcription. These enzymes which were initially found in Escherichia coli have attracted considerable attention as target molecules for cancer therapy. Nowadays, there are several topoisomerase inhibitors in the market to treat or at least control the progression of cancer. However, significant toxicity, low solubility and poor pharmacokinetic properties have limited their wide application and these characteristics need to be improved. Nano-delivery systems have provided an opportunity to modify the intrinsic properties of molecules and also to transfer the toxic agent to the target tissues. These delivery systems leads to the re-introduction of existing molecules present in the market as novel therapeutic agents with different physicochemical and pharmacokinetic properties. This review focusses on a variety of nano-delivery vehicles used for the improvement of pharmacological properties of topoisomerase inhibitors and thus enabling their potential application as novel drugs in the market.

Nigella sativa L., Supplementary Plant with Anticholinesterase Effect for Cognition Problems: A Kinetic Study.

BACKGROUND: The average lifespan and the aging population are rising worldwide. So Neurodegenerative Disease (ND) will be one of the most common challenges associated with this population and would be more prevalent in future. The use of Acetylcholinesterase (AChE) inhibitors is one of the most important strategies for memory impairment. Medicinal plants are the most known natural source for accessing the new therapeutic agents. OBJECTIVE: In this work, we aimed to study in vitro anticholinesterase effect of different concentrations (10, 100, 250, 500, 750 and 1000 µg/ml) of total extract of N. sativa (NTE) and its separated fractions and to study the kinetic of AChE enzyme in the presence of two concentrations of NTE (10 and 100 µg/ml). METHODS: Maceration method was used for NTE preparation and different fractions of Petroleum Ether (PTE), Chloroform (CHF) and Methanol (MF). NTE, fractions and the main component of the plant, Thymoquinone (TQ), were assayed for AChE inhibition, using Ellman's method. Kinetic study of the AChE enzyme was studied in the presence of NTE at 10 and 100 µg/ml using Linweaver- Burk plot too. RESULTS: NTE and all the separated fractions inhibited AChE enzyme in a concentration-dependent manner. The greatest inhibition was shown by CHF and PEF fractions (86.97% and 79.99% at 1000 µg/ml, respectively). With less intensity, NTE, TQ and MF exhibited 76.32%, 68.98 % and 48.39% enzyme inhibition at 1000µg/ml, respectively. The least IC50 value was due to CHF fraction in AChE inhibition (98.28 ± 6.74 µg/ml). Kinetic profile exhibited the mixed mode of AChE inhibition by NTE. This indicates that a particular substance could not be responsible for AChE inhibition, and probably a collection of phytochemicals are involved in this process. CONCLUSIONS: N. sativa is a good candidate for seeking the new anticholinesterase agent and could be considered as a good supplement for the health of the elderly.

Zataria multiflora Boiss. extract improves spatial memory and learning capacity in scopolamine-induced amnesic rats.

OBJECTIVE: Zataria multiflora (Zm) has been proposed for memory enhancing in Persian traditional medicine; but to now, no study has been carried out in this field yet. The aim of this research was to study the plant effect on spatial memory in scopolamine-induced amnesia and investigate in vivo anticholinesterase effect of Zm. MATERIAL AND METHODS: Aerial parts of the plant were extracted with methanol and standardized on the basis of rutin content. Male rats received three doses of Zm extract (100, 200 and 400 mg/kg, intraperitoneal (ip) for 7 days) and 30 min after the latest dose, scopolamine (1 mg/kg) was administered to animals. Learning capacity and spatial memory were studied using morris water maze (MWM) and passive avoidance test (PAT) methods. Anticholinesterase activity was studied using Ellman's method. Physostigmine (0.3 mg/kg) and piracetam (200 mg/kg) were used as positive controls. RESULTS: All doses of Zm extract significantly decreased the distance and time spent to find the platform in MWM and increased the time latency in PAT test. In both MWM and PAT tests, the highest effect of Zm was observed at 200 mg/kg which was in accordance with AChE inhibitory effect of the plant. CONCLUSION: Our findings indicate that Zm has anti-amnesic effect and might improve memory deficit through anticholinesterase activity.

Nanoparticles Targeting STATs in Cancer Therapy.

Over the past decades, an increase in the incidence rate of cancer has been witnessed. Although many efforts have been made to manage and treat this life threatening condition, it is still one of the leading causes of death worldwide. Therefore, scientists have attempted to target molecular signaling pathways involved in cancer initiation and metastasis. It has been shown that signal transducers and activator of transcription (STAT) contributes to the progression of cancer cells. This important signaling pathway is associated with a number of biological processes including cell cycle, differentiation, proliferation and apoptosis. It appears that dysregulation of the STAT signaling pathway promotes the migration, viability and malignancy of various tumor cells. Hence, there have been many attempts to target the STAT signaling pathway. However, it seems that currently applied therapeutics may not be able to effectively modulate the STAT signaling pathway and suffer from a variety of drawbacks such as low bioavailability and lack of specific tumor targeting. In the present review, we demonstrate how nanocarriers can be successfully applied for encapsulation of STAT modulators in cancer therapy.

Autophagy Modulators: Mechanistic Aspects and Drug Delivery Systems.

Autophagy modulation is considered to be a promising programmed cell death mechanism to prevent and cure a great number of disorders and diseases. The crucial step in designing an effective therapeutic approach is to understand the correct and accurate causes of diseases and to understand whether autophagy plays a cytoprotective or cytotoxic/cytostatic role in the progression and prevention of disease. This knowledge will help scientists find approaches to manipulate tumor and pathologic cells in order to enhance cellular sensitivity to therapeutics and treat them. Although some conventional therapeutics suffer from poor solubility, bioavailability and controlled release mechanisms, it appears that novel nanoplatforms overcome these obstacles and have led to the design of a theranostic-controlled drug release system with high solubility and active targeting and stimuli-responsive potentials. In this review, we discuss autophagy modulators-related signaling pathways and some of the drug delivery strategies that have been applied to the field of therapeutic application of autophagy modulators. Moreover, we describe how therapeutics will target various steps of the autophagic machinery. Furthermore, nano drug delivery platforms for autophagy targeting and co-delivery of autophagy modulators with chemotherapeutics/siRNA, are also discussed.

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications.

Bleeding is the most serious complication of warfarin anticoagulation therapy and is known to occur even at patients with therapeutic international normalized ratio (INR) range. Recently, it has been shown that microRNAs play a significant role in pharmacogenetics by regulating genes that are critical for drug function. Interaction between microRNAs and these target genes could be affected by single-nucleotide polymorphisms (SNPs) located in microRNA-binding sites. This study focused on 3'-untranslated region (3'-UTR) SNPs of the genes involved in the warfarin action and the occurrence of bleeding complications in an Iranian population receiving warfarin. A total of 526 patients under warfarin anticoagulation therapy with responding to the therapeutic dose and maintenance of the INR in the range of 2.0-3.5 in three consecutive blood tests were included in the study. Four selected 3'-UTR SNPs (rs12458, rs7294, rs1868774 and rs34669593 located in GATA4, VKORC1, CALU and GGCX genes, respectively) with the potential to disrupt/eliminate or enhance/create microRNA-binding site were genotyped using a simple PCR-based restriction fragment length polymorphism (PCR-RFLP) method. Patients with the rs12458 AT or TT genotypes of the GATA4 gene had a lower risk of bleeding compared to patients with the AA genotype (adjusted OR: 0.478, 95% CI: 0.285-0.802, P= 0.005, OR: 0.416, 95% CI: 0.192-0.902, P= 0.026, respectively). 3'-UTR polymorphisms in other genes were not significantly associated with the risk of bleeding complications. In conclusion, the SNP rs12458A>T in the 3'UTR region of GATA4 is associated with the incidence of warfarin-related bleeding at target range of INR, likely by altering microRNA binding and warfarin metabolism. Further genetics association studies are needed to validate these findings before they can be implemented in clinical settings.

Shedding light on gene therapy: Carbon dots for the minimally invasive image-guided delivery of plasmids and noncoding RNAs - A review.

Recently, carbon dots (CDs) have attracted great attention due to their superior properties, such as biocompatibility, fluorescence, high quantum yield, and uniform distribution. These characteristics make CDs interesting for bioimaging, therapeutic delivery, optogenetics, and theranostics. Photoluminescence (PL) properties enable CDs to act as imaging-trackable gene nanocarriers, while cationic CDs with high transfection efficiency have been applied for plasmid DNA and siRNA delivery. In this review, we have highlighted the precursors, structure and properties of positively charged CDs to demonstrate the various applications of these materials for nucleic acid delivery. Additionally, the potential of CDs as trackable gene delivery systems has been discussed. Although there are several reports on cellular and animal approaches to investigating the potential clinical applications of these nanomaterials, further systematic multidisciplinary approaches are required to examine the pharmacokinetic and biodistribution patterns of CDs for potential clinical applications.

Necrotic, apoptotic and autophagic cell fates triggered by nanoparticles.

Nanomaterials have gained a rapid increase in use in a variety of applications that pertain to many aspects of human life. The majority of these innovations are centered on medical applications and a range of industrial and environmental uses ranging from electronics to environmental remediation. Despite the advantages of NPs, the knowledge of their toxicological behavior and their interactions with the cellular machinery that determines cell fate is extremely limited. This review is an attempt to summarize and increase our understanding of the mechanistic basis of nanomaterial interactions with the cellular machinery that governs cell fate and activity. We review the mechanisms of NP-induced necrosis, apoptosis and autophagy and potential implications of these pathways in nanomaterial-induced outcomes. Abbreviations: Ag, silver; CdTe, cadmium telluride; CNTs, carbon nanotubes; EC, endothelial cell; GFP, green fluorescent protein; GO, graphene oxide; GSH, glutathione; HUVECs, human umbilical vein endothelial cells; NP, nanoparticle; PEI, polyethylenimine; PVP, polyvinylpyrrolidone; QD, quantum dot; ROS, reactive oxygen species; SiO2, silicon dioxide; SPIONs, superparamagnetic iron oxide nanoparticles; SWCNT, single-walled carbon nanotubes; TiO2, titanium dioxide; USPION, ultra-small super paramagnetic iron oxide; ZnO, zinc oxide.