The relation between ACKR4 and CCR7 genes expression and breast cancer metastasis.

AIMS: Breast cancer is the most severe malignant tumor in women. Chemokines and their receptors appear to be implicated in tumorigenesis and metastatic pattern. Also the scavenger atypical chemokine receptors are emerging as crucial regulators for the availability of chemokines. Therefore the aim of the present study is to evaluate the expression of CCR7, ACKR4 and their ligand; CCL21 in human breast cancer. MAIN METHODS: In this study, RT-PCR was done to detect the expression of CCR7 and ACKR4 in 50 non-metastatic and 30 metastatic breast cancer tissue. Also CCL21 level in the serum of study group was detected by ELISA. The expression of all markers is compared to 80 control healthy individual. KEY FINDINGS: Our results revealed the increase in expression of CCR7 and CCL21 level in metastatic group compared to non-metastatic and control groups while ACKR4 expression is significantly increased in breast tissues of non-metastatic patients compared to both control and metastatic groups. Also there was significant positive correlation between CCR7 expression and CCL21 level in cancer patients and significant negative correlation between ACKR4 and both CCR-7 and CCL21 in both non-metastatic and metastatic cancer groups. SIGNIFICANCE: Thus, it might be elucidating that ACKR4 and CCR7 could be a novel target for tumor therapy as targeting the chemokine-receptors axis might represent a powerful tool to prevent infiltration and metastasis and consequently improve cancer prognosis and treatment.

A novel protective role of sacubitril/valsartan in cyclophosphamide induced lung injury in rats: impact of miRNA-150-3p on NF-κB/MAPK signaling trajectories.

Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.

Therapeutic effect of liraglutide on expression of CTGF and BMP-7 in induced diabetic nephropathy.

INTRODUCTION: Diabetic nephropathy (DN) is one of the critical complications of diabetes mellitus and the main cause of chronic renal dysfunction. The pathogenic mechanism causing the disease remains unclear and there is a lack of effective treatment methods so novel strategies are needed for DN management. The aim of this study, therefore, is to evaluate the effect of liraglutide as glucagon-like peptide-1 analogue and its underlying mechanisms on induced DN in rats MATERIALS AND METHODS: Sixty rats were divided into control group, diabetic group, and liraglutide-treated group. At the end of experiment, renal CTGF and BMP-7 messeger RNA expression were determined. Blood sugar, serum urea, and creatinine were measured. Also, histopathological changes were studied. RESULTS: Liraglutide can improve renal alterations associated with diabetes as it reduced CTGF expression and increased BMP-7 expression. In the same time, it could improve histopathological changes and renal function tests. CONCLUSION: These findings influence the beneficial use of liraglutide for the management of DN in patients with diabetes mellitus.

Effect of experimentally induced hypertension on cerebellum of postmenopausal rat.

Cerebellum seems to be a specific target for both the decrease of estrogen and hypertension in menopause. The aim of this study was to investigate the hypertension and menopause-induced changes in rat's cerebellar cortex and the possible mechanisms of these changes. Rats were divided into four groups: the sham-operated control (SC-group), the ovariectomized (OVX-group), the hypertensive (H-group), and the ovariectomized-hypertensive (OVX-H-group) group. The mean arterial pressure (MAP), serum nitric oxide (NO), lipid peroxides and antioxidant catalase enzyme levels were assayed. Cerebellar tissue homogenization for analysis of lipid peroxides, antioxidant catalase enzyme, tumor necrosis factor-α (TNF-α), and estradiol was done. Quantification of adrenomedullin (AM) and interleukin-10 (IL-10) mRNA was also done. Cerebella were processed for histological, immunohistochemical and transmission electron microscopic examination. In the OVX-group, insignificant structural and biochemical changes were observed compared with the SC-group apart from the significantly increased lipid peroxides and decreased NO and catalase levels in serum. The H-group showed an elevated lipid peroxides and TNF-α levels, reduced catalase level, numerous degenerated Purkinje cells, vacuolations of the neuropil, some axonal degeneration, and few ghosts in the granular cell layer (GL). However, in OVX-H-group, oxidative stress, inflammation, and cerebellar damage were exacerbated and cerebellar estrogen was reduced associated with reduction in GL thickness and decreased Purkinje cells number. Most axoplasms had degenerated neurofilaments with abnormal myelination. The immunoexpression of glial fibrillary acidic protein were significantly increased in both OVX-group and H-group and significantly decreased in OVX-H group. Gene expression of AM and IL-10 were increased in cerebellar tissues of H-group compared with the SC-group but it was significantly decreased in OVX-H-group compared with H-group. Taken together, postmenopausal rats with hypertension suffered from structural cerebellar changes than rats with only hypertension or estrogen deficiency separately due to augmentation of the increased oxidative stress markers and the proinflammatory cytokines (TNF-α) with down regulation of the anti-inflammatory cytokine (IL-10) and the blood pressure regulator, AM. These suggested that high blood pressure is a critical factor for postmenopausal cerebellum.

Effect of histone deacetylase inhibitor on epithelial-mesenchymal transition of liver fibrosis.

Liver fibrosis is an excessively reversible wound healing process and the fibrotic disorder is the activation of hepatic stellate cell that requires extensive alterations in gene expression. As reversible deacetylation of histone proteins modulate gene expression, we examined the effect of valproic acid (VPA) as selective histone deacetylase inhibitor on CCl-4 induced liver fibrosis. Thirty rats were divided into three equal groups; control group, fibrotic group and VPA-treated group. The rats were sacrificed after 6 weeks of liver fibrosis induction. The histopathological effect on liver tissue was examined. The expression of α-SMA and Smad-4 mRNA and serum levels of TGF-ß1, alanine aminotransferase, and aspartate aminotransferase were determined. Treatment of rats with VPA attenuated carbon tetrachloride-induced liver fibrosis. Moreover, α-SMA and Smad-4 expression was repressed under VPA treatment and both serum TGF-ß1 and liver enzymes were significantly decreased. The histone deacetylase inhibitor-1 VPA inhibits the epithelial-mesenchymal transition and affects hepatic stellate cell activation during liver fibrosis through downregulation of Smad4 and α-SMA expression which may serve as a promising agent in liver fibrosis treatment. © 2018 IUBMB Life, 70(6):511-518, 2018.

The molecular mechanisms of action of the endocrine disrupting chemical bisphenol A in the development of cancer.

The endocrine disrupting chemical (EDC) is an exogenous substance or mixture that alters the function of the endocrine system and consequently causes adverse effects in intact organisms. Bisphenol A (BPA), one of the most common endocrine disrupting chemicals is a carbon-based synthetic compound used in the production of water bottles, cans, and teeth suture materials. It is known to be a xenoestrogen as it interacts with estrogen receptors and acts as agonist or antagonist via estrogen receptor-dependent signaling pathways. BPA has been associated with serious health effects in humans and wildlife. It elicits several endocrine disorders and plays a role in the pathogenesis of several hormone-dependent tumors such as breast, ovarian, prostate cancer and others. More complicate to this picture, its effects rely on several and diverse molecular and epigenetic mechanisms that converge upon endocrine and reproductive systems. The present review gives an overview of general hazards of BPA, its epigenetic modifications and the molecular mechanisms of BPA action in different types of cancers as the increase in information about responses and action mechanisms of BPA may bring a better understanding of the risks of BPA exposure in humans and provide an important platform on which human health can be improved.

Investigating the Relationship between Insulin-like Growth Factor-1 (IGF-1) in diabetic mother's breast milk and the blood serum of their babies.

INTRODUCTION: Since research investigating IGF-1 levels in breast milk are few, the goal of this study was to analyze the IGF-1 levels in the breast milk of diabetic mothers as well as in the serum of their newborn babies and to identify what relationship exists between blood serum and IGF-1 milk levels through patient measurement of mothers and their babies. METHODS: This case control study was undertaken under the auspices of the Clinic of Neonatology at Al Minia University Pediatric Hospital over May 2012 through May 2013. With a total of 30 diabetic mothers and their babies forming the experimental group and the control group consisting of 15 non-diabetic mothers and their babies. A detailed medical history, anthropometric assessments, as well as the measurement of the baby's serum IGF-1 and their mother's breast milk IGF-1 levels were taken from all participants using ELSIA. The resulting data were analyzed via Statistical Package for the Social Sciences (SPSS) version 16 and measurements of descriptive statistics, t-test, Chi-square test, as well as the Pearson Correlation Coefficient. RESULTS: The Infants born to Diabetic Mothers (IDMs) demonstrated significantly greater anthropometric measurement. Both the serum levels and the milk IGF-1 levels as well as all of the physical measurements taken were found to have a positive correlation between the level of IGF-1 in mother's milk and all of the anthropometric measurements studied with the exception of delivered baby's length. CONCLUSION: Higher levels of IGF-1 are present in the milk of diabetic mothers and the blood serum of their babies and this characteristic could be used as a prenatal biomarker for macrosomia.

Effect of Hemin on Brain Alterations and Neuroglobin Expression in Water Immersion Restraint Stressed Rats.

In the brain, the heme oxygenase (HO) system has been reported to be very active and its modulation seems to play a crucial role in the pathophysiology of neurodegenerative disorders. Hemin as HO-1 inducer has been shown to attenuate neuronal injury so the goal of this study was to assess the effect of hemin therapy on the acute stress and how it would modulate neurological outcome. Thirty male albino rats were divided into three groups: control group and stressed group with six-hour water immersion restraint stress (WIRS) and stressed group, treated with hemin, in which each rat received a single intraperitoneal injection of hemin at a dose level of 50 mg/kg body weight at 12 hours before exposure to WIRS. Stress hormones, oxidative stress markers, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured and expressions of neuroglobin and S100B mRNA in brain tissue were assayed. Our results revealed that hemin significantly affects brain alterations induced by acute stress and this may be through increased expression of neuroglobin and through antioxidant effect. Hemin decreased blood-brain barrier damage as it significantly decreased the expression of S100B. These results suggest that hemin may be an effective therapy for being neuroprotective against acute stress.

Involvement of fibroblast-specific protein 1 (S100A4) and matrix metalloproteinase-13 (MMP-13) in CCl4-induced reversible liver fibrosis.

INTRODUCTION: The intense basic research on the molecular and cellular mechanisms of liver fibrosis regression intends to translate these findings into new therapies targeting such pathways in human liver disease. Fibrosis regression is rapidly initiated in mouse models of fibrosis within days after termination of the cause, so in this study, we investigated the expression of S100A4 and MMP-13 during liver fibrogenesis and remodeling. METHODS: Thirty rats were divided into three groups: control group, fibrotic group, and fibrotic resolution group (10 each). The rats were sacrificed 48h and 96h after cessation of CCL-4, respectively. Liver tissue levels of S100A4 mRNA and S100A4 protein, MMP-13 mRNA and serum levels of serum TGF-ß1, ALT and AST were determined. RESULTS: Expression of S100A4 was increased during fibrotic stage and declined during resolution which was in correlation with the pro-fibrotic marker TGF-ß1 with concordance about 90%, while MMP-13 expression increased in both stages reaching to 40 fold during resolution. CONCLUSION: These findings suggested that S100A4 level in the liver tissue was related positively with liver fibrosis making it a good marker for liver fibrogenesis and also a good target for novel antifibrotic strategies.

Genetic polymorphism of estrogen receptor alpha gene in Egyptian women with type II diabetes mellitus.

Estrogen might play an important role in type 2 diabetes mellitus pathogenesis. A number of polymorphisms have been reported in the estrogen receptor alpha gene including the XbaI and PvuII restriction enzyme polymorphisms. The aim of this study was to determine if ESRα gene polymorphisms are associated with type 2 diabetes mellitus and correlated with lipid profile. Ninety diabetic Egyptian patients were compared with forty healthy controls. ESRα genotyping of PvuII and XbaI was performed using restriction fragment length polymorphism analysis. Our study showed that there is more significant difference in the frequency of C and G polymorphic allele between patients and control groups in PvuII and XbaI respectively. Also carriers of minor C and G alleles of PvuII and XbaI gene polymorphisms were associated with increased fasting blood glucose and disturbance in lipid profile as there is an increase in total cholesterol, triglycerides and Low density lipoprotein. So findings of present study suggest the possibility that PvuII and XbaI polymorphisms in ERα are related to T2DM and with increased serum lipids among Egyptian population.

Mechanism of testicular protection of carvedilol in streptozotocin-induced diabetic rats.

AIMS: Male sub-fertility and infertility are major complications of diabetes mellitus. The non-selective ß-blocker carvedilol has been reported to have favorable effects on some of the diabetic complications based on its antioxidant and anti-apoptotic effects. This study aims to evaluate the possible testicular protective effect of carvedilol in streptozotocin (STZ)-induced diabetic rat model and its possible mechanisms. MATERIALS AND METHODS: Diabetes was induced by a single i.p. dose of 65 mg/kg of STZ. In parallel groups of diabetic rats, carvedilol in low and high doses (1 and 10 mg/kg/day orally) were administered for 4 weeks. Oxidative stress markers as reduced glutathione (GSH) and the product of lipid peroxidation; malondialdehyde (MDA) were evaluated in testicular homogenate. The level of expression of the apoptotic marker; caspase 3, was assessed using western blot, followed by densitometric analysis. RESULTS: Induction of diabetes caused distortion of histological normal testicular structure, with decrease (P < 0.05) in GSH and increase (P < 0.05) in MDA, as well as induction of caspase 3 expression. Carvedilol in low or high doses reverted diabetes-induced histological damage, restored antioxidant activity and ameliorated caspase 3 expression. CONCLUSION: Carvedilol confers testicular protection against diabetes-induced damage through antioxidant and anti-apoptotic mechanisms.