Uncovering the relationship between YAP/ WWTR1 (TAZ) genes expression and LncRNAs of SNHG15, HCP5 and LINC01433 in breast cancer tissues.

In spite of the decrease in breast cancer (BC) death rates, it has remained a significant public health concern. Dysregulation of the Hippo pathway contributes to breast cancer development and progression by enhancing cancerous cell proliferation, survival, invasion, and migration. Investigating the connection between specific lncRNAs (SNHG15, HCP5, and LINC01433) and YAP and WWTR1, and the impact of these lncRNAs on the expression of YAP and WWTR1 proteins in the Hippo pathway, may offer valuable understanding for BC diagnosis and treatment. Forty BC tissue samples were acquired from the Tumor Bank and utilized for RNA and protein extraction. Real-time PCR and western blotting techniques were performed to assess the gene and protein expressions, respectively. Correlations between variables and their associations with clinicopathological features in BC were evaluated using Mann-Whitney U or Student's t-test. Additionally, the analysis of the GEO database was utilized to validate the findings. In cancerous tissue, the up-regulation of YAP, WWTR1, HCP5, SNHG15, and Linc01433 at both the mRNA and protein levels corresponds to the findings in GEO datasets. A significant association was found between YAP and histological grade, while WWTR1 showed a correlation with family history and HER-2. The distinct and notable expression of YAP, WWTR1, SNHG15, HCP5, and Linc01433 in BC tissues, together with the results of combined ROC curve analysis derived from our finding and GEO database suggest that a combined panel of these 5 RNAs may have great potential in predicting of BC and its management.

Unveiling Arformoterol as a potent LSD1 inhibitor for breast cancer treatment: A comprehensive study integrating 3D-QSAR pharmacophore modeling, molecular docking, molecular dynamics simulations and in vitro assays.

Lysine Specific Demethylase 1 (LSD1) has been identified as a chromatin-modifying enzyme implicated in various cancer pathogeneses, highlighting the potential for novel epigenetic cancer treatments through the development of effective inhibitors. We employed 3D-QSAR pharmacophore modeling, molecular docking, and molecular dynamics simulations to identify a promising drug candidate for LSD1 inhibition. RMSD, RMSF, H-bond, and DSSP analysis demonstrated that ZINC02599970 (Arformoterol) and ZINC13453966 exhibited the highest LSD1 inhibitory potential. Experimental validation using MCF-7 and MDA-MB-231 cell lines revealed that Arformoterol displayed potent antiproliferative activity with IC50 values of 12.30 ± 1.48 µM and 19.69 ± 1.15 µM respectively. In contrast, the IC50 values obtained for the control (tranylcypromine) in exposure to MCF-7 and MDA-MB-231 cells were 104.6 ± 1.69 µM and 77 ± 0.67 µM, respectively. Arformoterol demonstrated greater LSD1 inhibitory potency in MCF-7 cells compared to MDA-MB-231 cells. Also, the expression of genes involved in chromatin rearrangement (LSD1), angiogenesis (VEGF1), cell migration (RORα), signal transduction (S100A8), apoptosis, and cell cycle (p53) were investigated. Arformoterol enhanced apoptosis and induced cell cycle arrest at the G2/M phase, both in MCF-7 and MDA-MB-231 cancer cells. Based on our findings, we propose that Arformoterol represents a promising candidate for breast cancer treatment, owing to its potent LSD1 inhibitory activity.

Granulosa cells from immature follicles exhibit restricted glycolysis and reduced energy production: a dominant problem in polycystic ovary syndrome.

PURPOSE: We hypothesized that immature oocytes are associated with impaired energy production in surrounding granulosa cells (GCs) in polycystic ovary syndrome (PCOS). Thus, this study investigated mitochondrial function, determined expression of glycolytic regulatory enzymes, and measured ATP levels in GCs of PCOS patients. METHODS: GCs were isolated from forty-five PCOS patients and 45 control women. Intracellular concentration of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), the rate of glycolysis, total antioxidant capacity (TAC), activities of catalase (CAT) and superoxide dismutase (SOD), and ATP level were measured in GCs. The gene expression and protein levels of glycolytic enzymes (hexokinase, muscular phosphofructokinase, platelet derived phosphofructokinase, and muscular pyruvate kinase) were determined. Association of GC energy level with oocyte maturation was further validated by measuring glycolysis rate and ATP level in GCs isolated from mature and immature follicles from new set of fifteen PCOS patients and 15 controls. RESULTS: PCOS patients showed higher ROS level, decreased TAC, reduced CAT and SOD activities, and lower Δψm together with reduced expression of key glycolytic enzymes. ATP concentration and biochemical pregnancy were lower in PCOS compared with control group. ATP levels were found to be significantly correlated with ROS and Δψm (r = - 0.624 and r = 0.487, respectively). GCs isolated from immature follicles had significantly lower ATP levels and rate of glycolysis compared with the GCs separated from mature follicles in both PCOS patients and control. CONCLUSION: Declined energy due to the mitochondrial dysfunction and restrained glycolysis in GCs is associated with the immature oocytes and lower biochemical pregnancy in PCOS.

The Association of Mitochondrial Translocator Protein and Voltage-Dependent Anion Channel-1 in Granulosa Cells with Estradiol Levels and Presence of Immature Follicles in Polycystic Ovary Syndrome.

Background: Granulosa cells (GCs) play key roles in oocyte maturation by providing required estradiol (E2). Since the presence of immature oocytes has been reported in cases with polycystic ovary syndrome (PCOS), in this study, the levels of mitochondrial membrane transporter proteins involved in E2 synthesis were determined. E2 concentration and parameters of oxidative status were also measured in follicular fluids of PCOS women. Methods: Forty-three women with PCOS and 43 healthy women who were candidates for IVF procedure due to their husbands' infertility were enrolled in this case-control study. The gene expression and protein levels of mitochondrial translocator protein (TSPO) and voltage-dependent anion channel 1 (VDAC1) were determined in GCs using RT-qPCR and immunocytochemistry assay, respectively. E2 level was measured with electrochemiluminescence, whereas total cholesterol, total antioxidant capacity (TAC), total oxidant status (TOS), and malondialdehyde (MDA) were determined using colorimetric methods in follicular fluids. Data were analyzed using unpaired t-test or Mann-Whitney U test, and Spearman's correlation coefficient. Results: VDAC1 and TSPO were significantly lower in mRNA (p<0.05) and protein levels (p<0.001) of PCOS patients. PCOS patients had lower cholesterol, estradiol, and TAC levels, and higher TOS and MDA contents. E2 level had direct correlation with VDAC1, TSPO, and TAC while it was negatively correlated with TOS, oxidative stress index (OSI), and MDA (p<0.001). Higher E2 levels were associated with higher numbers of high-quality oocytes and conceived embryos (p<0.001). Conclusion: Decreased E2 levels and increased oxidative stress in the follicular fluid may be the cause of immature oocytes in PCOS cases.

The Association of Oxidative Stress and Reactive Oxygen Species Modulator 1 (ROMO1) with Infertility: A Mini Review.

Infertility is one of the disorders that worries many couples around the world, although novel and molecular methods can be used to cure this disease in different stages. One of the factors that causes infertility in men and women is the increased oxidative stress within the cells, which can lead to damage in zygote formation. ROMO1 is one of the most important proteins in the production of reactive oxygen species. This protein can enhance oxidative stress in the cells and body through cellular pathways, such as TNF-α and NF-κB routes, which will eventually lead to many diseases, especially infertility. We engage several international databases by using keywords; ROMO1, Infertility, and Reactive Oxygen Species, and gained a great quantity of information about ROMO1, Infertility, and Oxidative Stress. Although not proven, it is hypothesized that ROMO1 might elevate oxidative stress by activating NF-κB pathway in the cells, furthermore, TNF-α can arouse ROMO1 that can end up with apoptosis and cell death, which consequently can have a lot of disturbing effects on the body, especially the reproductive system. To sum up, revealing the exact cellular and molecular mechanisms of ROMO1-dependent TNF-α and NF-κB pathways in the pathogenesis of infertility might find interesting therapeutic and management strategies for this disorder.

Effects of curcumin and metformin on oxidative stress and apoptosis in heart tissue of type 1 diabetic rats.

Introduction: Hyperglycemia enhances oxidative stress and apoptosis and induces damages in heart tissue. Based on antioxidant properties of curcumin and metformin, we hypothesized that these agents may exhibit cardioprotective effects by attenuating oxidative stress and modulating expression of the genes involved in apoptosis in type-1 diabetes. Methods: Thirty-six male rats were randomly divided into six groups; (N): control; (D): streptozotocin-induced diabetic rats; (D+Cur50) and (D+Cur150): diabetic rats treated with 50 and 150 milligram of curcumin per kilogram of body weight (mg/kg.bw), respectively; (D+Met300) and (D+Met500): diabetic rats received 300 and 500 mg/kg.bw of metformin, respectively. Heart tissues were dissected and gene expression levels of Bax, Bcl-2, and caspase-3 were analyzed. Total anti-oxidant capacity (TAC), total oxidant status (TOS), and malondialdehyde (MDA) level, and activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. Results: Enhancement in TOS, OSI, and MDA levels as well as increased in the activity of CAT and reduction in SOD and GPx activities were observed in diabetic group (D) compared with control rats. Treatment of diabetic animals with either curcumin or metformin normalized TOS, OSI, and MDA levels and restored CAT, SOD, and GPx activities. Diabetes caused extensive damages in heart tissue of rats (group D) and increased expression of caspase-3 and Bax genes and enhanced ratio of Bax/Bcl-2 expression compared with controls. Treatment with curcumin or metformin mitigated histopathological changes and dampened apoptosis by normalizing Bax and caspase-3 expression. Conclusion: Curcumin and metformin modulated diabetes-induced cardiac damage probably by reducing oxidative stress.

The Association of COVID-19 and Reactive Oxygen Species Modulator 1 (ROMO1) with Oxidative Stress.

There is no denying that the massive spread of COVID-19 around the world has worried everyone. The virus can cause mild to severe symptoms in various organs, especially the lungs. The virus affects oxidative stress in the cells. Reactive Oxygen Species modulator 1 (ROMO1) is one of the most important mitochondrial proteins that plays a critical regulatory role in the production of Reactive Oxygen Species (ROS). According to the studies, COVID-19 can promote oxidative stress through some important pathways, for instance, TNF-α and NF-κB routes. Furthermore, ROMO1 is closely related to these pathways and its dysfunction may affect these routes, then promote oxidative stress, and ultimately cause tissue damage, especially in the lungs. Another factor to consider is that the TNF-α and NF-κB pathways are associated with ROMO1, COVID-19, and oxidative stress. To summarize, it is hypothesized that COVID-19 may increase oxidative stress by affecting ROMO1. Understanding the exact molecular mechanisms of ROMO1 in the pathogenesis of COVID-19 can pave the way to find better therapeutic strategies.

Aspartate Aminotransferase-To-Platelet Ratio Index: a Potential Predictor of Prognosis in the Most Common Types of Cirrhosis.

BACKGROUND: Cirrhosis is often an asymptomatic disease. Its early diagnosis before the development of life-threatening complications is an important step to prevent the progression of the disease. The aim of the present study was the identification of parameters that are significantly changed in cirrhosis, are not affected by the cause of cirrhosis, and are associated with fatal complications of cirrhosis. METHODS: Demographic and pre-transplant ultrasound and laboratory findings were reviewed in patients with viral- (n = 27), autoimmune hepatitis- (n = 27), alcohol- (n = 18), primary sclerosing cholangitis- (PSC) (n = 36), and nonalcoholic steatohepatitis-related cirrhosis (n = 42). RESULTS: Among laboratory findings, only the aspartate aminotransferase-to-platelet ratio index (APRI) value in cirrhotic patients was significantly higher than that of healthy individuals (p < 0.001) and, meanwhile, its value was not different among cirrhotic patients with various etiologies (p = 0.240) but was associated with the ascites, as a cirrhosis life-threatening complication (p < 0.001). CONCLUSIONS: The APRI has acceptable potential to predict prognosis in cirrhosis. So, it can be a possible parameter to the prediction of the lethal complications of cirrhosis.

NLRP3-inflammasome activation is associated with epithelial-mesenchymal transition and progression of colorectal cancer.

OBJECTIVES: Since activation of NLRP3 inflammasome results in the production of interleukin-1ß (IL 1ß) and initiation of inflammation as the key players in development of cancer, this study investigated possible activation of NLRP3 inflammasome during the progression of colorectal cancer (CRC) and evaluated the role of NLRP3 inflammasome in epithelial-mesenchymal transition (EMT) process. MATERIALS AND METHODS: Tissue samples were collected from cancerous (test) and adjacent normal tissues (control) of forty-three male CRC patients (18 grade I and 25 grade III). The gene expression and protein levels were determined by qRT PCR and Western blotting, respectively, and tissue morphological was examined by histopathology. RESULTS: The gene and protein expression levels of transforming growth factor-ß (TGF ß), IL 1ß, nuclear factor κB (NF κB), NLRP3, and caspase-1, as well as the enzyme activity of caspase-1, were significantly increased in CRC. mRNA and protein levels of TGF-ß, mature IL 1ß, NF κB, and NLRP3 were higher in patients with grade III. EMT markers N cadherin, vimentin, and MMP 9 markedly increased in CRC, and were higher in grade III than grade I, whereas expression of E-cadherin declined by the progression of CRC. NLRP3 protein level was inversely correlated with E-cadherin whereas it positively was correlated with IL 1ß, active NF κB, N cadherin, vimentin, and MMP 9. CONCLUSION: This study for the first time showed that activation of NLRP3 inflammasome contributed to the progression of CRC and is correlated with the EMT process. Although the present study showed that EMT markers are positively correlated with tumor grade, further investigations are required to strongly link the EMT markers to the progression of CRC.

Transitional cell carcinoma matrix stiffness regulates the osteopontin and YAP expression in recurrent patients.

Cells translate the mechanosensing of extracellular matrix component dysregulation and stiffness into the signal transduction including Osteopontin (OPN) through the Hippo pathway. But how extracellular matrix (ECM) component dysregulation and stiffness are ultimately linked to transitional cell carcinoma (TCC) development remains poorly understood. This study was aimed to evaluate the possible links between ECM component alteration after cancer surgery and OPN and Yes-associated protein (YAP) expression in TCC and adjacent tissues. In this study, we used 50 TCC (25 newly diagnosed and 25 recurrent) and 50 adjacent tissues to determine the tissue stiffness using atomic force microscopy. The mRNA expression of SPP1, Indian hedgehog (IHH), and YAP was also determined using qRT-PCR. Western blotting and ELISA were performed to assess the tissue and serum levels of OPN, respectively. To assess the glycoproteins and elastic fibers content, Periodic Acid Schiff, and Verhoeff-Van Gieson Staining were performed, respectively. Matrix stiffness was markedly higher in TCCs than adjacent tissues (p < 0.05). Gene expression analysis showed that YAP, SPP1, and IHH genes were upregulated in TCC tissues (p < 0.05). Additionally, the OPN protein overexpression was observed in the tissue and the serum of TCC patients (p < 0.05). We also found that glycoproteins, elastic fibers content of recurrent TCC tissues was remarkably higher as compared to adjacent tissues (p < 0.05). Our results suggest that glycoproteins and elastic fibers content modulation and ECM stiffness may upregulates the expression of YAP, SPP1 and IHH genes, and possibly contribute to the TCC development and relapse.

Favorable effects of dill tablets and Ocimum basilicum L. extract on learning, memory, and hippocampal fatty acid composition in hypercholesterolemic rats.

OBJECTIVES: Hypercholesterolemia is correlated with brain amyloid-ß (Aß) deposition and impaired cognitive functions and contributes to Alzheimer's disease. Effects of cholesterol-lowering dill tablets and aqueous extract of Ocimum basilicum L. (basil) on learning and memory and hippocampus fatty acid composition were examined. mRNA levels of the genes involved in cholesterol homeostasis were also determined in high-cholesterol diet (HCD) fed rats. MATERIALS AND METHODS: Forty male Wistar rats were allocated to 4 groups: rats fed chow diet (C); rats fed high-cholesterol (2%) diet (HCD); rats treated with HCD+300 mg/kg dill tablets (HCD+Dill); and finally, rats fed HCD and treated with 400 mg/kg basil aqueous extract (HCD+basil). Treatment was carried out for 16 weeks. Hippocampus Aß(1-42) level was determined. Spatial and passive avoidance tests were used to examine cognitive functions. Hippocampal FA composition was assessed by gas chromatography. Basil aqueous extract was analyzed by GC-double mass spectroscopy (GC-MS/MS) and expression of LXR-α, LXR-ß, and ABCA1 genes was assessed by qRT-PCR. RESULTS: Dill tablets and basil extract remarkably ameliorated serum cholesterol (P<0.001), retarded hippocampal accumulation of Aß, and attenuated HCD-induced memory impairment. Hippocampus FA composition did not change but serum cholesterol was found positively correlated with hippocampus Aß(1-42) (P<0.001), total n 6 PUFA (P=0.013), and Aß(1-42) showed correlation with the ratio of n6 to n3 PUFA. At least 70 components were identified in basil aqueous extract. CONCLUSION: Dill tablets and aqueous extract of basil attenuated the hypercholesterolemia-induced memory impairment by lowering serum cholesterol and hippocampus amyloid deposits, and probably beneficial in AD adjuvant therapy.

Urinary epidermal growth factor is a novel biomarker for early diagnosis of antibody mediated kidney allograft rejection: A urinary proteomics analysis.

Although antibody mediated rejection (AMR) accounts for 20-30% of all acute renal allograft rejections, introducing biomarkers for a timely detection of allograft rejection has been remained challenging. This study investigated novel diagnostic biomarkers of AMR by examining of urine proteome in renal transplant patients. Thirty-six patients with kidney transplantation including 22 AMR patients and 14 patients with stable renal function (control group) were enrolled in this study. Urinary samples were collected and Label free quantification (LFQ) proteomics technique was applied on urine samples and data was subjected to Random Forest (RF) algorithm to predict main candidate proteins contributing in AMR. Finally, applicability of candidate diagnostic biomarkers was evaluated in new sets of AMR subjects, stable patients and healthy volunteers. A total of 1020 proteins were detected in urine proteome. RF algorithm predicted 20 differentially expressed proteins with the highest sensitivity and specificity and combination of EGF, COL6A, and NID-1 was identified as possible panel for early diagnosis of AMR. Applicability of EGF as diagnostic biomarker was validated in urine samples of independent set of AMR subjects. This is the first urinary proteomics study in AMR patients demonstrating that urinary EGF might be used as early diagnostic biomarker for AMR. SIGNIFICANCE: Renal antibody mediated rejection (AMR) accounts for 20-30% of all acute rejections of allografted kidneys. Although several possible biomarkers have been proposed to predict AMR, ineffectiveness of current urinary biomarkers in early diagnosing of AMR patients and in distinguishing AMR subjects from patients with stable kidney function casts doubts on their applicability in clinic. Here for the first time and based on the analysis of urinary proteome we showed that uEGF and uEGF/Cr might be candidate biomarkers to predict AMR with high diagnostic power.

Imbalance in thioredoxin system activates NLRP3 inflammasome pathway in epicardial adipose tissue of patients with coronary artery disease.

Atherosclerosis is the leading cause of death worldwide and has in part an inflammatory basis. Since epicardial adipose tissue (EAT) is in close contact with coronary arteries we hypothesized that an imbalance in thioredoxin-1 (TRX-1) and thioredoxin interacting protein (TXNIP) in EAT, activates NLRP3 inflammasome and promotes production of IL-1ß, leading to the development of atherosclerosis. Thirty-eight patients with coronary artery disease (CAD) and thirty patients with no clinical signs of atherosclerosis who underwent open-heart surgery for valve replacement were classified as CAD and control groups, respectively. Biopsy samples from EAT were collected and expression of TXNIP, TRX-1, NLRP3 and IL-1ß genes were assessed using qRT-PCR. Tissue protein levels of TXNIP and TRX-1 were determined by Western blotting while ELISA was applied to measure IL-1ß. Haematoxylin and eosin staining was used for histological examination. mRNA and protein levels of TXNIP in EAT were significantly higher in patients with CAD compared with control group, whereas CAD patients showed lower TRX-1 gene and protein expression. In addition, in CAD patients the NLRP3 gene expression was almost doubled and IL-1ß significantly increased at the both mRNA and protein levels. Enhancment in NLRP3 gene expression and TXNIP protein levels were accompanied with the increase in IL-1ß protein level whereas TRX-1 protein content showed a negative correlation with IL-1ß level. Concurrent increase in TXNIP, NLRP3, and IL-1ß suggests possible involvement of thioredoxin system in the activation of NLRP3 inflammasome, production of IL-1ß, and the presence of inflammation in CAD patients.

Downregulation of Sirt1 is correlated to upregulation of p53 and increased apoptosis in epicardial adipose tissue of patients with coronary artery disease.

The higher expression level of p53 in epithelial adipose tissue (EAT) has previously been reported in atherosclerosis. Since we hypothesized that the expression of p53 is modulated by Sirt1, the aim of this study was to determine the expression levels of Sirt1 and p53 and to investigate their correlation to apoptosis in EAT of patients with coronary artery disease (CAD). Thirty-five patients with more than 50 % stenosis in at least one of the main coronary arteries were considered as CAD group while 29 patients with no clinical signs of atherosclerosis who underwent open-heart surgery for valve replacement were classified as control group. EAT biopsy samples were collected from all participants during surgery. Sirt1, p53, Bax, and Bcl-2 gene expression levels were determined in EAT by qRT-PCR and Western blotting was carried out to assess Sirt1 and p53 protein levels. Hematoxylin and eosin staining was used for histopathological analysis. mRNA and protein levels of Sirt1 in EAT were significantly lower in patients with CAD compared with control group, whereas CAD patients showed greater p53 gene and protein expressions. In addition, inverse correlations were observed between Sirt1 and p53 at both mRNA and protein levels. The Bax and ratio of Bax/Bcl-2 gene expressions were higher in CAD group, but no difference was observed in Bcl-2 expression. Histopathological analysis showed apoptotic bodies and infiltrated immune cells in EAT of CAD group. Our results suggest that the Sirt1-p53 axis may involve in atherosclerosis by promotion of apoptosis.

Carvacrol Downregulates Lysyl Oxidase Expression and Ameliorates Oxidative Stress in the Liver of Rats with Carbon Tetrachloride-Induced Liver Fibrosis.

In the current study, we aimed to investigate the effect of carvacrol on the suppression of liver fibrosis progression through targeting lysyl oxidase (LOX) expression. The rats received carbon tetrachloride (CCl4) intraperitoneally and carvacrol orally for 10 weeks. Liver damage was evaluated by measuring the serum level of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase and hepatic oxidative stress parameters including total antioxidant capacity, total thiol group and total oxidant status spectrophotometry and malondialdehyde fluorometrically. Extracellular deposition of collagen was detected using Masson's trichrome standing. Furthermore the gene expression of lysyl oxidase homolog 2 (Loxl2) was analyzed using quantitative reverse transcription-polymerase chain reaction. And then the protein level of LOX was detected in liver tissue by western blot method. Carvacrol administration normalized serum biochemical parameters and improved oxidative stress status in liver homogenate of CCl4 treated rats. Collagen fiber bundles in interlobular spaces were decreased remarkably by carvacrol treatment. Also, carvacrol downregulated hepatic gene expression of Loxl2 and protein level of LOX. Our data clearly revealed that carvacrol suppresses progression of liver fibrosis development via attenuating of liver damage and oxidative stress status as well as via downregulation of hepatic gene expression of Loxl2 and protein level of LOX.

Dill tablet and Ocimum basilicum aqueous extract: Promising therapeutic agents for improving cognitive deficit in hypercholesterolemic rats.

High-cholesterol diet (HCD) is correlated with Alzheimer's disease (AD) and impairment of memory. This study investigated beneficial therapeutic effects of Dill tablet and Ocimum basilicum (Basil) aqueous extract on hypercholesterolemia-induced cognitive deficits and oxidative stress in hippocampus tissues of rats. Hippocampal Aß(1-42) level was measured. The gene expression levels of superoxide dismutase and inducible-nitric oxide synthase were determined in hippocampus. Cognitive functions were examined and oxidative status was evaluated in serum and hippocampus. Phytochemical properties and in vitro antioxidant activity of Basil extract were assessed. HCD significantly increased serum cholesterol, induced deposition of Aß plaque, altered hippocampus morphology, and impaired memory function, whereas receiving Basil extract or Dill tablet increased antioxidant potency in serum and hippocampus and normalized HCD-induced deleterious effects. Basil extract and Dill tablet may exhibit their beneficial effects in AD by lowering serum cholesterol and evoking antioxidant system in the brain. PRACTICAL APPLICATIONS: Dill tablet and Basil aqueous extract lowered serum cholesterol in hypercholesterolemic animal models, therefore, they can be used as hypocholesterolemic agents. These edible herbs significantly retarded deposition of Aß plaque and normalized hippocampal morphology, thus, they favorably protected hippocampus tissue from deleterious effects-induced by hypercholesterolemia. Dill tablet and Basil aqueous extract also corrected oxide-redox balance and normalized HCD-induced oxidative stress to some extent and significantly improved impairments in learning and memory suggesting that these medicinal plants can be considered as surrogate therapeutic agents for the synthetic medicines in the treatment of AD and in postponement of its complications.

Effects of post-training administration of LY341495, as an mGluR2/3 antagonist on spatial memory deficit in rats fed with high-fat diet.

High-fat diets (HFDs) adversely influence glutamate metabolism and neurotransmission. The precise role of the group II metabotropic glutamate receptors (mGluR2/3) antagonist on spatial memory deficit following consumption of HFD has not yet been clarified. Therefore, in this study, we examined the effects of post-training administration of mGluR2/3 antagonism; LY341495 on spatial memory in rats fed with HFD (for 10 weeks) by using Morris Water Maze (MWM) task. The training session for testing memory acquisition in MWM consisted of 4 trials per day for 4 consecutive days. Twenty-four hours after the last training session the spatial probe test (retention) was given. Intraperitoneal injection (i.p) injection of LY341495 was done 30 min before probe test. Our results showed that 10 weeks consumption of HFD had no significant effect on escape latency and swimming distance in memory acquisition. Our finding showed that consumption of a HFD leads to reference memory impairment in the probe test. HFD animals spent less time in the target zone in compare with control animals. Also, LY341495 improved HFD-induced reference memory (retention) impairment. HFD animals treated with LY341495 spent more time in the target zone in compare with HFD animals. Escape latencies to find the visible platform during visual task were same in all experimental groups, indicating no visual impairment in the animals. We propose that a HFD may act through mGluR2/3 within the brain to reduce synaptic plasticity, which impairs memory retrieval, and post-training administration of LY341495 can reduce HFD-induced reference memory impairment.

Tissue stiffness contributes to YAP activation in bladder cancer patients undergoing transurethral resection.

Changes in the cellular microenvironment play a critical role in the development of bladder cancer (BC). Yes-associated protein (YAP), a central mediator of the Hippo pathway, functions as a nuclear sensor of mechanotransduction that can be induced by stiffness of the extracellular matrix (ECM), including stiffness resulting from surgical manipulations. We aimed to clarify the possible association between surgically-related ECM stiffness and YAP activation in BC patients. We compared 30 bladder cancer tissues with grade II (n = 15 recurrent and n = 15 newly diagnosed) with 30 adjacent healthy tissues. Atomic force microscopy showed that patients with recurrent BC had stiffer ECM than newly diagnosed patients (P < 0.05). Gene expression profiles showed that ß1 integrin (ITGB1), focal adhesion kinase (FAK), CDC42, and YAP were upregulated in cancerous tissues (P < 0.05); additionally, ß1 integrin activation was confirmed using a specific antibody. Nuclear localization of YAP was higher in recurrent cancerous tissues compared with newly diagnosed and it was positively associated with higher stiffness (P < 0.05). Our results suggest that postsurgery-induced ECM stiffness can influence integrin-FAK-YAP activity and thereby YAP trafficking to the nucleus where it contributes to BC progression and relapse.

Changes in the distribution of etiologies of cirrhosis among patients referred for liver transplantation over 11 years in Iran.

BACKGROUND AND AIM: Cirrhosis is a major public health problem worldwide. The prevalence of cirrhosis is various in different geographical regions. The aim of the present study was to determine the distribution of the etiologies of cirrhosis and their proportional changes through recent 11 years in Iran. METHODS: In this retrospective, observational study, the data of cirrhotic patients who have been listed for liver transplantation in the Namazi Transplant Center (Shiraz, Iran) between January 2006 and December 2016 were analyzed. Demographic and clinical data of the patients including model for end-stage liver disease score, year of registration, and the etiologic diagnosis for each patient were retrieved. RESULTS: The ratio of males to females was the highest (2.6:1) in patients with age over 50 years. Of 4891 patients, hepatitis B virus cirrhosis had the highest frequency (23.53%) and alcoholic cirrhosis had the lowest frequency (1.70%). The percentages of waiting list patients with hepatitis B virus (34.48%-17.48%) (P < 0.001), autoimmune hepatitis (12.64%-8.50%) (P = 0.037), and alcoholic cirrhosis (2.30%-1.10%) were decreased (P = 0.008) and the percentages of waiting list patients with cholestatic (12.64%-25.20%) and nonalcoholic steatohepatitis cirrhosis (0.77%-8.82%) were increased over 11 years (both P < 0.001). Hepatitis B virus and autoimmune hepatitis cirrhosis were the most prevalent in male and female patients, respectively. CONCLUSION: The results of the present study showed an increase in the frequency of cholestasis and nonalcoholic steatohepatitis cirrhosis and therefore it should be considered in the health policy implementation.

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis.

The pivotal role of the extracellular matrix (ECM) as both a cause and consequence of liver fibrosis is striking. However, mechanotransducer molecules and profibrogenic factors induced by liver stiffness are still unclear. The current study aimed to investigate liver stiffness and its correlation with the expression of the transcriptional coactivator with PDZ-binding motif (TAZ) and serum osteopontin (OPN) in human cirrhosis. In this case-control study, liver tissue stiffness was determined using atomic force microscopy in cirrhotic livers (n = 38) of different etiologies and in controls (n = 10). Immunohistochemical and qRT-PCR analyses were performed to analyze TAZ expression. Besides, western blotting and ELISA were performed to assess liver Indian hedgehog and serum OPN levels, respectively. Liver stiffness, TAZ expression, and hepatic gene expression and serum protein levels of OPN were significantly increased in patients with cirrhosis compared with the control groups (all P < 0.001), specifically in autoimmune- and alcohol-related cirrhosis. In cirrhotic patients, liver stiffness was significantly associated with the expression of nuclear TAZ and OPN. The correlation between matrix stiffness as a mechanical property, TAZ as a potential mechanotransducer, and OPN as a matricellular factor suggests possible effects of mechanical features of the ECM on the expression of the aforementioned profibrogenic markers, which is predominant in autoimmune- and alcohol-related cirrhosis.