Circular RNAs: Epigenetic regulators of PTEN expression and function in cancer.

Epigenetic regulation of gene expression, without altering the DNA sequence, is involved in many normal cellular growth and division events, as well as diseases such as cancer. Epigenetics is no longer limited to DNA methylation, and histone modification, but regulatory non-coding RNAs (ncRNAs) also play an important role in epigenetics. Circular RNAs (circRNAs), single-stranded RNAs without 3' and 5' ends, have recently emerged as a class of ncRNAs that regulate gene expression. CircRNAs regulate phosphatase and tensin homolog (PTEN) expression at various levels of transcription, post-transcription, translation, and post-translation under their own regulation. Given the importance of PTEN as a tumor suppressor in cancer that inhibits one of the most important cancer pathways PI3K/AKT involved in tumor cell proliferation and survival, significant studies have been conducted on the regulatory role of circRNAs in relation to PTEN. These studies will be reviewed in this paper to better understand the function of this protein in cancer and explore new therapeutic approaches.

Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients.

BACKGROUND: Coronary artery disease (CAD) is a devastating illness and a leading cause of death worldwide, primarily caused by atherosclerosis resulting from a genetic-environmental interaction. This study aimed to investigate the relationship between the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) polymorphisms, lipid profile parameters, and CAD risk in a southeast Iranian population. METHODS: A total of 400 subjects (200 CAD patients with hyperlipidemia and 200 healthy controls) were enrolled in this case-control study. Five selected polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: For all single nucleotide polymorphisms (SNPs), the population under study was in the Hardy-Weinberg equilibrium. The T-risk allele frequency of rs2228570 was associated with an increased risk of CAD. The TT and CT genotypes of rs2228570 had also been associated with the risk of CAD. Additionally, the TT genotype was associated with higher serum low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels. The GG genotype of the rs3736234 was associated with higher body mass index (BMI) and triglyceride (TG) levels, and the AA genotype of the rs708272 was associated with higher HDL-c levels. Based on these findings, we propose that the VDR (rs2228570) polymorphism was associated with serum HDL-c and LDL-c levels and may serve as potential risk factors for CAD within the Iranian population. Moreover, rs3736234 and rs708272 influence the concentrations of TG and HDL-c, respectively. CONCLUSION: These findings provided insights into the complex interplay between genetic variations, cardiovascular risk, and lipid metabolism.

MiRNA-miRNA interaction network in peripheral blood of patients with myocardial infarction: a gene expression meta-analysis.

In recent years, investigations have revealed that microRNAs (miRNAs) can bind together and form a miRNA-miRNA-mRNA regulatory network that alters the consequence of miRNA-mRNA interaction. If we consider the miRNA that binds to mRNA as the primary miRNA and the miRNA that binds to the primary miRNA as the secondary one, secondry miRNAs can act as master regulators upstream of primary miRNAs and their target mRNAs. One of the distinguishing characteristics of secondary miRNAs as master regulators within a diverse set of differentially expressed genes is the absence of direct target mRNA for them. Instead, these master regulators exclusively govern the regulation of miRNAs that target specific mRNAs. Through in silico analysis, we identified 18 miRNAs among 385 differentially expressed miRNAs (DEmiRNAs) with no direct target mRNAs among 58 differentially expressed mRNAs (DEmRNAs) in peripheral blood of patients with myocardial infarction (MI). Instead, these secondary miRNAs targeted 9 primary miRNAs that had 36 direct targets among 58 DEmRNAs. We found that one primary miRNA might be regulated by more than one secondary miRNAs and each secondary miRNA can target more than one primary miRNAs. Among identified miRNA-miRNA-mRNA networks miR-188-5p/miR-299-3p/natural killer cell granule protein (NKG7), miR-200a-3p/miR-199b-5p/granzyme B (GZMB), and miR-377-3p/miR-581/oviductal glycoprotein 1 (OVGP1) exhibited higher scors in terms of expression levels (>2-fold increase or decrease) and strengh of interactions (ΔG < -5). Given the extensive network of miRNA interactions, focusing on master regulators opens up avenues for identifying key regulatory nodes for more effective therapeutic strategies.

The effect of saffron and its extracts on the treatment of breast cancer: A narrative review.

Breast cancer (BC) is the most prevalent malignancy in women and the second most common disease worldwide, affecting approximately one million individuals annually. Despite the efficacy of conventional chemotherapy, medication resistance and adverse effects limit its effectiveness, leading researchers to explore alternative treatments, including herbal remedies. Saffron, a well-known spice derived from the Crocus sativus L. plant, has shown potential as a BC treatment. The active components of saffron exhibit anti-cancer properties by inducing apoptosis, inhibiting cell division, and modulating signaling pathways implicated in cancer development, such as PI3K/AKT, NF-κB, and MAPK. Clinical findings suggest that saffron can alleviate chemotherapy-induced symptoms, reduce serum tumor marker levels, and enhance quality of life. Preliminary clinical trials are investigating the safety and efficacy of saffron in treating BC, with recent evidence indicating that recommended doses of saffron supplementation are well-tolerated and safe. This review provides an overview of the anti-tumor effects of saffron and its unique chemical composition in BC. However, further research and clinical studies are imperative to fully comprehend the potential of saffron in adjuvant therapy for BC patients.

CircPAN3/miR-221/PTEN axis and apoptosis in myocardial Infarction: Quercetin's regulatory effects.

The circular RNA/microRNA/mRNA axis is a new layer of non-coding RNA(ncRNA)-based regulatory gene expression networks upstream of numerous cell signaling pathways. Circular RNAPAN3 (circPAN3) is involved in autophagy, fibrosis and apoptosis which are responsible for the reduction incardiac functional capacityfollowingmyocardial infarction(MI). However, the molecular mechanism of circPAN3 association with apoptosis is unknown. In addition, the relationship between quercetin as a cardioprotective factor in MI and circular RNA-dependent regulatory pathways has not yet been elucidated. MI was induced in Wistar rats using the left anterior descending artery (LAD) ligation method. One day after surgery, quercetin (30 mg/kg) was injected intraperitoneal (IP) every other day for two weeks. The expression of circPAN3 was increased in the MI group (P < 0.05). The increase in circPAN3 was accompanied by a decrease in miR-221 (P < 0.0001), an increase in PTEN (P < 0.0001), and cleaved caspase 3 (P < 0.001). Quercetin effectively reduced the expression of circPAN3 (P < 0.05), PTEN (P < 0.0001), and cleaved caspase 3 (P < 0.001), and increased the expression of miR-221 (P < 0.0001) and the ratio of p-AKT to p-PI3K (P < 0.001). The circPAN3/miR-221/PTEN pathway is an ncRNA-dependent apoptotic pathway in MI cardiac tissue. Quercetin effectively modulated this pathway, resulting in a reduction of cardiac tissue death and improvement in cardiac function after MI. This suggests that the circPAN3/miR-221 axis plays a role in apoptosis in MI, and quercetin can act as a protective candidate by modulating this pathway.

Autophagy in combination therapy of temozolomide and IFN-γ in C6-induced glioblastoma: role of non-coding RNAs.

Aim: We predicted the modulation of autophagy and apoptosis in response to temozolomide (TMZ) and IFN-γ based on changes in the expression of non-coding RNAs in C6-induced glioblastoma (GBM). Materials & methods: Each rat received an intraperitoneal injection of TMZ (7.5 mg/kg) and/or IFN-γ (50,000 IU). Results: The reduced expression of H19 and colorectal neoplasia differentially expressed (CRNDE) was associated with a reduction in autophagy in response to TMZ, IFN-γ and TMZ + IFN-γ therapy, whereas the decreased level of miR-29a (proapoptotic miRNA) was associated with an increase in apoptosis. Conclusion: It appears that H19 promotes switching from autophagy to apoptosis in response to combination therapy of TMZ and IFN-γ through the miR-29a/autophagy-related protein 9A (ATG9A) pathway in C6-induced GBM.

Temozolomide (TMZ) is a drug for people with brain cancer. It can make it hard for patients to learn and think, and it can also make the drug stop working, which lets the tumor keep growing. Researchers are looking for other drugs or things that can be taken with TMZ to stop this from happening. In this study, we used a protein called interferon (IFN), which helps fight cancer. We gave mice with brain cancer both TMZ and IFN, and saw that the tumor cells died and the tumor got smaller. We also looked at how IFN and TMZ changed the genetic material of the mouse brain, called RNA. But we need to test this on people to be sure it works.

Effect of l -Dopa in acute temozolomide-induced cognitive impairment in male mice: a possible antineuroinflammatory role.

Temozolomide is used commonly in the treatment of some types of cancers, but it may also result in cognitive impairments such as memory deficits. l -Dopa, a well known medicine for the central nervous system, has been shown to have positive effects on some cognitive disorders. Here we sought to investigate the effect of l -Dopa on temozolomide-induced cognitive impairments. BALB/c mice were subjected to 3-days temozolomide and 6-days concomitant l -Dopa/benserazide administration in six groups (control, l -Dopa 25 mg/kg, l -Dopa 75 mg/kg, temozolomide, temozolomide +  l -Dopa 25 mg/kg, and temozolomide +  l -Dopa 75 mg/kg). Open field test, object location recognition, novel object recognition test, and shuttle-box test were carried out to determine the locomotor, anxiety-like behavior, and memory function of subjects. TNF-α and brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus was measured by real-time PCR. Mice treated with temozolomide showed recognition memory impairment, along with hippocampal TNF-α and BDNF mRNA expression level raise, and detection of histological insults in hematoxylin and eosin hippocampal slides. Mice that received temozolomide +  l -Dopa showed normal behavioral function and lower TNF-α and BDNF hippocampal mRNA expression levels, and histologically normal hippocampal CA1 region in comparison with mice in the temozolomide group. Our results provide evidence that l -Dopa prevents temozolomide-induced recognition memory deficit in mice at the acute phase probably via l -Dopa antineuroinflammatory effects.

Investigating unique genes of five molecular subtypes of breast cancer using penalized logistic regression.

Background: Breast cancer (BC) is the most common cancer and the fifth cause of death in women worldwide. Exploring unique genes for cancers has been interesting. Patients and Methods: This study aimed to explore unique genes of five molecular subtypes of BC in women using penalized logistic regression models. For this purpose, microarray data of five independent GEO data sets were combined. This combination includes genetic information of 324 women with BC and 12 healthy women. Least absolute shrinkage and selection operator (LASSO) logistic regression and adaptive LASSO logistic regression were used to extract unique genes. The biological process of extracted genes was evaluated in an open-source GOnet web application. R software version 3.6.0 with the glmnet package was used for fitting the models. Results: Totally, 119 genes were extracted among 15 pairwise comparisons. Seventeen genes (14%) showed overlap between comparative groups. According to GO enrichment analysis, the biological process of extracted genes was enriched in negative and positive regulation biological processes, and molecular function tracking revealed that most genes are involved in kinase and transferring activities. On the other hand, we identified unique genes for each comparative group and the subsequent pathways for them. However, a significant pathway was not identified for genes in normal-like versus ERBB2 and luminal A, basal versus control, and lumina B versus luminal A groups. Conclusion: Most genes selected by LASSO logistic regression and adaptive LASSO logistic regression identified unique genes and related pathways for comparative subgroups of BC, which would be useful to comprehend the molecular differences between subgroups that would be considered for further research and therapeutic approaches in the future.

Treatment for Myocardial Infarction: In Vivo Evaluation of Curcumin-Loaded PEGylated-GQD Nanoparticles.

ABSTRACT: Curcumin (Cur) has been suggested as a complementary treatment for cardiovascular diseases. Its efficiency, however, is modest due to poor biocompatibility. This study examined the effects of curcumin loaded on polyethylene glycol-graphene quantum dots (Cur-PEG-GQDs) on hemodynamic and cardiac function in rats with myocardial infarction (MI). The study groups included control, MI, MI+Cur-3, MI + Cur-7, MI + Cur-15, MI + PEG-GQDs-5, MI + PEG-GQDs-10, MI + Cur-PEG-GQDs-5, and MI + Cur-PEG-GQDs-10. MI was established by left anterior descending artery ligation. Two weeks after intraperitoneal administration of vehicle, Cur, PEG-GQDs, and Cur-PEG-GQDs, blood pressure and heart contractility indices were measured. Triphenyl tetrazolium chloride, colorimetry, and clinical laboratory methods were used to measure the infarct size, the oxidant and antioxidant content, and the kidney and liver function parameters, respectively. In the MI animals, Cur-7, PEG-GQDs-10, Cur-PEG-GQDs-5, and Cur-PEG-GQDs-10 recovered systolic blood pressure, diastolic blood pressure, left ventricular systolic pressure, and ±dp/dt max disturbances and reduced myocardial infarct size, fibrosis, and left ventricular end-diastolic pressure. Curcumin lowered antioxidant markers and elevated 1 oxidant marker in the heart in a dose-dependent manner. Although Cur-PEG-GQDs-5 and Cur-PEG-GQDs-10 reduced curcumin's oxidative stress effects, the superoxide dismutase, glutathione peroxidase, and total antioxidant capacity levels were significantly lower in Cur-PEG-GQDs-5 and Cur-PEG-GQDs-10 groups compared with the MI group. Malondialdehyde levels were lower in Cur-PEG-GQDs-5 and -10 groups compared with the Cur-3, Cur-7, and Cur-15 groups. The glutathione/glutathione disulfide ratio improved in the groups treated by Cur-7, PEG-GQDs-10, Cur-PEG-GQDs-5, and Cur-PEG-GQDs-10. The findings indicated that Cur-PEG-GQDs mitigated MI-induced cardiac dysfunction. However, because of the increase in oxidative stress in the heart, nonclassic mechanisms may be involved in the beneficial effect of Cur-PEG-GQDs on MI-induced cardiac dysfunction.

Effects of the Ethanol and Ethyl Acetate Extracts of Terminalia chebula Retz. on Proliferation, Migration, and HIF-1α and CXCR-4 Expression in MCF-7 Cells: an In Vitro Study.

Over recent years, much attention has been devoted to the field of screening natural products and/or their novel structures because of reversing cancer progression. The current research work was intended to explore the cytotoxic activity of ethanol and ethyl acetate extracts of dried fruit of Terminalia chebula Retz. (T. chebula) in MCF-7 cell line. High-performance thin-layer chromatographic (HPTLC) method and Folin-Ciocalteu colorimetric techniques were performed. Anti-proliferative activities of T. chebula fruit extracts on the MCF-7 cell line were evaluated using MTT assay. Effects of both extracts on the migration of MCF-7 cells and the size of MCF-7-derived spheroids were also evaluated. Moreover, antioxidant properties were measured by DPPH and FRAP methods. Western blotting was used to measure the HIF-1α and CXCR-4 protein levels. Chebulagic acid, gallic acid, chebulinic acid, and ellagic acid were found as major compounds in both extracts. The total phenolic contents based on gallic acid equivalent (GAE) in the ethanol and ethyl acetate extracts of T. chebula were found to be 453.68 ± 0.31 and 495.12 ± 0.43 mg GAE/g dry weight of the extract, respectively. Both extracts exerted a significant dose- and time-dependent cytotoxicity effect on MCF-7 cells. They also had a marked negative effect on the average size of MCF-7-derived spheroids and their migration rate. None of the extracts exhibited stronger antioxidant activities than vitamin C. Furthermore, both extracts at a concentration of 125 µg/ml could meaningfully decrease the expression levels of HIF-1α and CXCR-4 in MCF-7 cells. These data represent that T. chebula may be a valuable medicinal resource in the regulation of breast cancer proliferation, growth, and metastasis.

Isoflavone daidzein ameliorates renal dysfunction and fibrosis in a postmenopausal rat model: Intermediation of angiotensin AT1 and Mas receptors and microRNAs 33a and 27a.

Objectives: Chronic kidney disease (CKD), accompanied by renal dysfunction, fibrosis, and apoptosis, is highly prevalent in postmenopausal women. We tested the hypothesis that isoflavone daidzein may ameliorate renal dysfunction and fibrosis through angiotensin II type 1 (AT1R) and angiotensin 1-7 (MasR) receptors in association with microRNAs 33a and 27a. Materials and Methods: Two weeks before the initiation of the experiments, rats (n=84) underwent ovariectomy (OVX). Then, unilateral ureteral obstruction (UUO) was performed in OVX rats, and animals were allocated to the following groups (n=21): sham vehicle (dimethyl sulfoxide; DMSO 1%), UUO vehicle, UUO+17ß-estradiol (E2), and UUO+daidzein. Each group encompassed three subgroups (n=7) treated with saline, A779 (MasR antagonist), or losartan (AT1R antagonist) for 15 days. The fractional urine excretion of sodium (FENa+) and potassium (FEK+), renal failure index (RFI), renal interstitial fibrosis (RIF index), glomerulosclerosis, miR-33a, and miR-27a expressions and their target genes were analyzed. Apoptosis was measured via cleaved caspase-3 immunohistochemistry. Results: UUO increased kidney weight, FENa+, FEK+, urine calcium, RFI, RIF index, glomerulosclerosis, and cleaved caspase-3. Moreover, expression of renal miR-33a and miR-27a, collagen3A1 mRNA, and protein were up-regulated post-UUO. Daidzein treatment alleviated the harmful effects of UUO especially in co-treatment with losartan. They also masked the anticipated worsening effects of A779 on UUO. Conclusion: Compared with E2, daidzein efficiently ameliorated renal dysfunction, fibrosis, and apoptosis through modulation of miR-33a and miR-27a expression and their crosstalk with AT1R and MasR. Therefore, daidzein might be a promising candidate for treating CKD in postmenopausal and older women.

The crosstalk between long non-coding RNAs and the hedgehog signaling pathway in cancer.

Hedgehog (Hh) is a conserved signaling pathway that is involved in embryo development as well as adult tissue maintenance and repair in invertebrates and vertebrates. Abnormal activation of this pathway in various types of malignant drug- and apoptosis-resistant tumors has made it a therapeutic target against tumorigenesis. Thus, understanding the molecular mechanisms that promote the activation or inhibition of this pathway is critical. Long non-coding RNAs (lncRNAs), a subclass of non-coding RNAs with a length of > 200 nt, affect the expression of Hh signaling components via a variety of transcriptional and post-transcriptional processes. This review focuses on the crosstalk between lncRNAs and the Hh pathway in carcinogenesis, outlines the broad role of Hh-related lncRNAs in tumor progression, and illustrates their clinical diagnostic, prognostic, and therapeutic potential in tumors.

Perillyl alcohol and quercetin modulate the expression of non-coding RNAs MIAT, H19, miR-29a, and miR-33a in pulmonary artery hypertension in rats.

BACKGROUND: Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery hypertension (PAH). LncRNA H19, myocardial infarction-associated transcript (MIAT), miR-29a, and miR-33a have been suggested as potential targets for treating arterial hypertension. We explored the expression pattern of non-coding RNAs H19, MIAT, miR-29a, and miR-33a in monocrotaline (MCT)-induced PAH rats. Moreover, we investigated whether perillyl alcohol (PA) and quercetin (QS), two plant derivatives with beneficial effects on PAH-induced abnormalities, act through regulating the expression of these non-coding RNAs. METHODS: Male Wistar rats (n = 30) were divided into five groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered three weeks after induction of PAH. H&E staining and qRT-PCR were performed to assess arteriole wall thickness and gene expression, respectively. RESULTS: Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) increased in MCT and MCT + Veh. groups compared to the control group (in both P < 0.001). QS and PA decreased RVSP and RVH significantly. Wall thickness and fibrosis score in the MCT group (score 3) increased compared to the control group (score 0). PA and QS ameliorated wall thickness and fibrosis to score 1 (mild). Also, the expression of miR-29a and miR-33a decreased in the PAH group (in both, P < 0.001). Treatment with PA and QS decreased the expression of H19 (P < 0.001) and MIAT (P < 0.01) and increased the expression of miR-29a (P < 0.01) and miR-33a significantly (P < 0.05 for QS and P < 0.001 for PA). CONCLUSIONS: The beneficial effects of PA and QS on PAH-induced abnormalities were exerted through returning the dysregulated expression of H19, MIAT, miR-29a, and miR-33a to normal levels in rats with MTC-induced PAH. This study emphasized the therapeutic potential of PA and QS in PAH. However, more detailed investigations are needed to clarify the underlying molecular mechanisms.

Investigation of genes and pathways involved in breast cancer subtypes through gene expression meta-analysis.

BACKGROUND: Molecular-based studies have revealed heterogeneity in Breast cancer BC while also improving classification and treatment. However, efforts are underway to distinguish between distinct subtypes of breast cancer. In this study, the results of several microarray studies were combined to identify genes and pathways specific to each BC subtype. METHODS: Meta-analysis of multiple gene expression profile datasets was screened to find differentially expressed genes (DEGs) across subtypes of BC and normal breast tissue samples. Protein-protein interaction network and gene set enrichment analysis were used to identify critical genes and pathways associated with BC subtypes. The differentially expressed genes from meta-analysis was validated using an independent comprehensive breast cancer RNA-sequencing dataset obtained from the Cancer Genome Atlas (TCGA). RESULTS: We identified 110 DEGs (13 DEGs in all and 97 DEGs in each subtype) across subtypes of BC. All subtypes had a small set of shared DEGs enriched in the Chemokine receptor bind chemokine pathway. Luminal A specific were enriched in the translational elongation process in mitochondria, and the enhanced process in luminal B subtypes was interferon-alpha/beta signaling. Cell cycle and mitotic DEGs were enriched in the basal-like group. All subtype-specific DEG genes (100%) were successfully validated for Luminal A, Luminal B, ERBB2, and Normal-like. However, the validation percentage for Basal-like group was 77.8%. CONCLUSION: Integrating researches such as a meta-analysis of gene expression might be more effective in uncovering subtype-specific DEGs and pathways than a single-study analysis. It would be more beneficial to increase the number of studies that use matched BC subtypes along with GEO profiling approaches to reach a better result regarding DEGs and reduce probable biases. However, achieving 77.8% overlap in basal-specific genes and complete concordance in specific genes related to other subtypes can implicate the strength of our analysis for discovering the subtype-specific genes.

Beneficial effects of PEGylated graphene quantum dot on arrhythmias induced by myocardial infarction.

Arrhythmias are one of the leading causes of early death following myocardial infarction (MI) and heart failure. Graphene derivatives have emerged as an therapeutic target that have electrical conductivity. The study aimed to evaluate the impacts of polyethylene glycol-graphene quantum dots (GQDs-PEG) on arrhythmias created by MI in the rat. Animals were randomly assigned to five groups of sham, MI, and MI + GQDs-PEG at doses of 5, 10, and 20 mg/kg. MI was induced by the closure of the left anterior descending artery. The day after MI, animals were administered vehicle (phosphate buffered saline) or GQDs-PEG at different doses every other day for 2 weeks. On day 15, electrocardiogram (ECG), mean arterial pressure (MAP), and heart contractility indices were recorded by the PowerLab data acquisition system. GQDs-PEG 20 mg/kg increased contractility and improved the reduction of MAP in the MI group. The prolonged QT and QTc intervals, inverted T wave, and deviated ST segment were modified by GQDs-PEG 10 and 20 mg/kg in rats with MI. The amplitude of the Q wave was also decreased in a dose-dependent manner in the GQDs-PEG-treated rats. The results demonstrated that 2 weeks of treatment with GQDs-PEG normalized ECG abnormalities and improved left ventricular dysfunction in rats with MI.

PEGylated Graphene Quantum Dot Improved Cardiac Function in Rats with Myocardial Infarction: Morphological, Oxidative Stress, and Toxicological Evidences.

INTRODUCTION: The biocompatibility and potential application of graphene-based nanomaterials in biomedicine have been documented. The effects of polyethylene glycol-graphene quantum dots (GQDs-PEG) on cardiac function in rats with myocardial infarction (MI) were examined. METHODS: Wistar rats were randomly assigned to two main groups, each consisting of sham-Veh., MI-Veh., and MI+GQDs-PEG at doses of 5, 10, and 20 mg/kg. MI was induced by the closure of the left anterior descending (LAD) coronary artery. After MI, GQDs-PEG were injected at different doses IP every other day for two weeks. In the end, hemodynamic and heart contractility indices were assessed. The levels of myocardial MDA (malondialdehyde), SOD (superoxide dismutase), GPX (glutathione peroxidase), and TAC (total antioxidant capacity) were measured by the ELISA method. The serum ALP, ALT, AST, creatinine, and urea levels were measured using the photometric method. The infarct size was assessed by TTC staining. RESULTS: GQDs-PEG decreased the infarct size at doses of 10 and 20 mg/kg and recovered the MI-induced reductions of +dp/dt max and -dp/dt max in the study groups. GQDs-PEG normalized systolic blood pressure and left ventricular systolic pressure reduction at the dose of 20 mg/kg in the MI group. Heart SOD, GPX, and TAC increased in the GQDs-PEG 10 and 20 groups. Almost no signs of toxic effects due to GQDs-PEG administration were observed on the liver and kidneys. CONCLUSIONS: The results provided clear evidence that GQDs-PEG improve cardiac performance and hemodynamic parameters in rats with MI by reducing oxidative stress. GQDs-PEG is proposed as a therapeutic target for the treatment of MI.

Quercetin, Perillyl Alcohol, and Berberine Ameliorate Right Ventricular Disorders in Experimental Pulmonary Arterial Hypertension: Effects on miR-204, miR-27a, Fibrotic, Apoptotic, and Inflammatory Factors.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the pathophysiology of PAH. As the current treatments cannot prevent the progression of the disease, we investigated whether 3 plant derivatives, namely perillyl alcohol (PA), quercetin (QS), and berberine (BBR), can improve RV function and affect the expression of miR-204, miR-27a, and biochemical factors in monocrotaline-induced PAH (MCT-PAH). Thirty-six rats were divided into control (CTL), MCT, MCT+Veh (vehicle), MCT+PA, MCT+QS, and MCT + BBR groups (n = 6 each). After inducing PAH using MCT (60 mg/kg), PA (50 mg/kg), QS (30 mg/kg), and BBR (30 mg/kg) were administrated daily for 3 weeks. miR-204 expression, total antioxidant capacity, and antiapoptotic protein Bcl-2 significantly declined in the RV of PAH rats, and PA, QS, and BBR treatment significantly compensated for these decreases. Proapoptotic protein Bax and p21 cell cycle inhibitor increased in the RV. All 3 herbal derivatives compensated for Bax increase, and BBR caused a decrease in p21. TNFα, IL-6, and malondialdehyde increased in the RV, and PA, QS, and BBR significantly counterbalanced these increases. miR-27a expression was not affected by MCT and plant derivatives. Overall, PA, QS, and BBR improved ventricular disorders in rats with PAH by decreasing inflammation, apoptosis, and fibrosis and increasing the antioxidant-to-oxidant ratio. Therefore, these herbal derivatives may be considered as target therapeutic goals for this disease either alone or in combination with current medications.

Curcumin loaded on graphene nanosheets induced cell death in mammospheres from MCF-7 and primary breast tumor cells.

Elimination of tumor cells is still a therapeutic challenge for breast cancer (BC) in men and women. Mammospheres serve as valuablein vitrotools for evaluating tumor behavior and sensitivity to anticancer treatments. Graphene nanosheets with unique physicochemical properties have been considered as potential biomedical approaches for drug delivery, bioimaging, and therapy. Graphene oxide (GO) and graphene quantum dots (GQDs) are suitable nanocarriers for hydrophobic and low bioaccessible anti-tumor materials like curcumin. Despite extensive studies on the potential application of graphene nanosheets in medicine, our knowledge of how different cells function and respond to these nanoparticles remains limited. Here, we evaluated cell death in mammospheres from MCF-7 and primary tumor cells in response to curcumin loaded on graphene nanosheets. Mammospheres were exposed to graphene oxide-curcumin (GO-Cur) and graphene quantum dots-curcumin (GQDs-Cur), and the incidence of cell death was evaluated by Hoechst 33342/propidium iodide double staining and flow cytometry. Besides, the expression of miR-21, miR-29a, Bax, and Bcl-2 genes were assessed using RT-qPCR. We observed, GO, and GQDs had no cytotoxic effect on Kerman male breast cancer/71 (KMBC/71) and MCF-7 tumor cells, while curcumin induced death in more than 50% of tumor cells. GO-Cur and GQDs-Cur synergistically enhanced anti-tumor activity of curcumin. Moreover, GQDs-Cur induced cell death in almost all cells of KMBC/71 mammospheres (99%;p< 0.0001). In contrast, GO-Cur induced cell death in only 21% of MCF-7 mammosphere cells (p< 0.0001). Also, the expression pattern of miR-21, miR-29a, and Bax/Bcl-2 ratio in KMBC/71 and MCF-7 mammospheres was different in response to GO-Cur and GQDs-Cur. Although KMBC/71 and MCF-7 tumor cells had similar clinical features and displayed similar responses to curcumin, more investigations are needed to clarify the detailed molecular mechanisms underlying observed differences in response to GO-Cur and GQDs-Cur.

High affinity of host human microRNAs to SARS-CoV-2 genome: An in silico analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by a novel betacoronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has attracted top health concerns worldwide within a few months after its appearance. Since viruses are highly dependent on the host small RNAs (microRNAs) for their replication and propagation, in this study, top miRNAs targeting SARS-CoV-2 genome and top miRNAs targeting differentially expressed genes (DEGs) in lungs of patients infected with SARS-CoV-2, were predicted. METHODS: All human mature miRNA sequences were acquired from miRBase database. MiRanda tool was used to predict the potential human miRNA binding sites on the SARS-CoV-2 genome. EdgeR identified differentially expressed genes (DEGs) in response to SARS-CoV-2 infection from GEO147507 data. Gene Set Enrichment Analysis (GSEA) and DEGs annotation analysis were performed using ToppGene and Metascape tools. RESULTS: 160 miRNAs with a perfect matching in the seed region were identified. Among them, there was 15 miRNAs with more than three binding sites and 12 miRNAs with a free energy binding of -29 kCal/Mol. MiR-29 family had the most binding sites (11 sites) on the SARS-CoV-2 genome. MiR-21 occupied four binding sites and was among the top miRNAs that targeted up-regulated DEGs. In addition to miR-21, miR-16, let-7b, let-7e, and miR-146a were the top miRNAs targeting DEGs. CONCLUSION: Collectively, more experimental studies especially miRNA-based studies are needed to explore detailed molecular mechanisms of SARS-CoV-2 infection. Moreover, the role of DEGs including STAT1, CCND1, CXCL-10, and MAPKAPK2 in SARS-CoV-2 should be investigated to identify the similarities and differences between SARS-CoV-2 and other respiratory viruses.

Perillyle alcohol and Quercetin ameliorate monocrotaline-induced pulmonary artery hypertension in rats through PARP1-mediated miR-204 down-regulation and its downstream pathway.

BACKGROUND: Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the pathophysiology of PAH. Perillyle alcohol (PA) and Quercetin (QS) are plant derivatives with antioxidant and anti-proliferative properties. We investigated the effect of PA and QS on PAP, expression of PARP1, miR-204, and their targets, HIF1α and NFATc2, in experimental PAH. METHODS: Thirty rats were divided into control, MCT, MCT + Veh, MCT + PA and MCT + QS groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered for 3 weeks after inducing PAH. PAP, lung pathology, expression of miRNA and mRNA, and target proteins were evaluated through right ventricle cannulation, H&E staining, real-time qPCR, and western blotting, respectively. RESULTS: Inflammation and lung arteriole thickness in the MCT group increased compared to control group. PA and QS ameliorated inflammation and reduced arteriole thickness significantly. miR-204 expression decreased in PAH rats (p < 0.001). PA (p < 0.001) and QS (p < 0.01) significantly increased miR-204 expression. Expression of PARP1, HIF1α, NFATc2, and α-SMA mRNA increased significantly in MCT + veh rats (all p < 0.001), and these were reduced after treatment with PA and QS (both p < 0.01). PA and QS also decreased the expression of PARP1, HIF1α, and NFATc2 proteins that had increased in MCT + Veh group. CONCLUSION: PA and QS improved PAH possibly by affecting the expression of PARP1 and miR-204 and their downstream targets, HIF1a and NFATc2. PA and QS may be therapeutic goals in the treatment of PAH.