Impact of breath hold on regional nodal irradiation and heart volume in field in left breast cancer adjuvant irradiation.

PURPOSE: Compared to the free-breathing technique, adjuvant left breast irradiation after breast-conserving surgery or mastectomy using the breath-hold method significantly reduces the heart mean dose, Left anterior descending artery, and ipsilateral lung doses. Movement with deep inspiration may also reduce heart volume in the field and regional node doses. MATERIALS AND METHODS: Pre-radiotherapy planning CT was performed in the free-breathing, and breath-hold techniques using RPM, demographic information, clinicopathological data, heart volume in the field, heart mean dose, LAD mean dose, and regional nodal doses were calculated in both free breathing and DIBH. Fifty patients with left breast cancer receiving left breast adjuvant radiation were enrolled. RESULTS: There was no significant difference in axillary LN coverage between the two techniques, except for SCL maximum dose, Axilla I node maximum dose, and Axilla II minimum dose in favor of the breath hold technique. The mean age was 47.54 years, 78% had GII IDC, 66% had positive LVSI results, and 74% of patients had T2. The breath hold strategy resulted in considerably decreased mean heart dose (p = 0.000), LAD dose (p = 0.000), ipsilateral lung mean dose (p = 0.012), and heart volume if the field (p = 0.013). The mean cardiac dosage and the dose of the LAD were significantly correlated (p = 0.000, R = 0.673). Heart volume in the field and heart mean dosage was not significantly correlated (p = 0.285, r = - 0.108). CONCLUSION: When compared to free breathing scans, DIBH procedures result in considerably reduced dosage to the OAR and no appreciable changes in dose exposure to regional lymph node stations in patients with left-sided breast cancer.

A Review of Endocrine Therapy in Early-stage Breast Cancer: The Journey From Crudeness to Precision.

Endocrine therapy (ET) is the standard of care for hormone receptor-positive early-stage breast cancer in the adjuvant setting. However, response to ET can vary across patient subgroups. Historically, hormone receptor expression and clinical stage are the main predictors of the benefit of ET. A "window of opportunity" trials has raised significant interest in recent years as a means of assessing the sensitivity of a patient's cancer to short-term neoadjuvant ET, which provides important prognostic information, and helps in decision-making regarding treatment options in a time-efficient and cost-efficient manner. In the era of genomics, molecular profiling has led to the discovery and evaluation of the prognostic and predictive abilities of new molecular profiles. To realize the goal of personalized medicine, we are in urgent need to explore reliable biomarkers or genomic signatures to accurately predict the clinical response and long-term outcomes associated with ET. Validation of these biomarkers as reliable surrogate endpoints can also lead to a revolution in the clinical trial designs, and potentially avoid the need for repeated tissue biopsies in the surveillance of disease response. The clinical potential of tumor genomic profiling marks the beginning of a new era of precision medicine in breast cancer treatment.

Impact of Extended Adjuvant Temozolamide Beyond 6 Months in the Management of Glioblastoma Patients.

OBJECTIVES: Our study aimed to assess the benefit of prolonging adjuvant temozolomide (TMZ) therapy beyond 6 cycles in glioblastoma multiform patients. MATERIALS AND METHODS: The medical records of 329 patients in 2 cancer centers in Egypt were reviewed from January 2008 to December 2018 who were diagnosed with diffuse gliomas. Data were collected on patient demographics, presenting complaints, tumor size, treatment modalities (extent of surgery, radiotherapy dose and technique, concomitant TMZ, and the number of adjuvant TMZ cycles), and reported adverse events. RESULTS: In the studied cohort, 105 patients were treated with adjuvant TMZ, 33 patients received <6 cycles (TMZL), 41 patients received the standard 6 cycles (TMZS), and 31 patients received >6 cycles (TMZE). Our results showed the median overall survival in the TMZL arm was 8.47 months compared with 15.83 months in the TMZS arm and 27.33 months in the TMZE arm ( P < 0.001). Furthermore, a median progression-free survival of 6.35 months was reported in the TMZL group versus, 12.7 and 22.90 months in (TMZS) and (TMZE) groups, respectively( P < 0.001). In the multivariate analysis, the extended adjuvant TMZ with a hazard ratio of 3.106 (95% CI: 2.43-14.46; P < 0.001) was statistically significantly associated with a better outcome. CONCLUSIONS: Extended adjuvant TMZ therapy beyond 6 cycles may significantly improve the progression-free survival and overall survival in patients with glioblastoma multiform.

Analytical dosimetric study of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for prostate cancer.

PURPOSE: The study aimed to compare the dosimetric results and treatment delivery efficiency among four techniques to explore the preferred technique in prostate treatment. MATERIALS AND METHODS: 7 IMRT, 9 IMRT, 1 ARC, and 2 ARC plans were created for 30 prostate cancer patients using the Eclipse™ treatment planning system (Varian Medical Systems). All the plans were designed to deliver 80.0 Gy in 40 fractions to the prostate planning target volume (PTV). Target coverage, organs at risk (OARs), number of monitor units, homogeneity, and conformity were compared across the four techniques to assess the quality of the plans. RESULTS: The study revealed better Planning Target Volume (PTV) dose coverage in the VMAT-2A than in the other plans. At the same time, VMAT-2A plans were found to be significantly lower in terms of Bladder and rectum doses than other techniques. In addition, VMAT has the advantage of considerably reducing the number of monitor units and treatment time. CONCLUSION: For prostate cancer, VMAT may offer a favorable dose gradient profile, conformity, and MU and treatment time compared to IMRT.

True aneurysm of the dorsalis pedis artery.

OBJECTIVES: Aneurysm of the pedal arteries is uncommon. I present a case of non-traumatic fusiform true aneurysm of the dorsalis pedis artery in an otherwise well 45-year-old man. Color flow duplex imaging revealed aneurysmal dilation, involving all layers of the artery wall, measuring 16.5 * 10 mm with irregular intraluminal thrombus across a 6.33-mm segment. Due to concerns over embolization, our patient underwent successful ligation of the dorsalis pedis artery. He had an uneventful post-operative recovery. METHODS: Case report. RESULTS: No postoperative complication or signs of ischemia. CONCLUSIONS: Treatment of asymptomatic dorsalis pedis artery aneurysm may be of value to prevent risk of thrombo-embolic complications, foot ischemia, or rupture without warning signs. Patency of the pedal arch is important to avoid foot ischemia in case of dorsalis pedis artery ligation.

Impact of breath-hold technique on incidence of cardiac events in adjuvant left breast cancer irradiation.

BACKGROUND: This study aims to compare the incidence of cardiac events and to identify its predictors in left breast cancer patients receiving adjuvant radiotherapy using breath-hold technique (DIBH) versus free breathing technique (FB). METHODS: We conducted a retrospective multi-center study of two arms; the free breathing arm included 208 patients who were treated with traditional radiotherapy treatment technique, while DIBH arm included 224 patients who were treated with breath-hold technique using The Varian Real-time Position Management (RPM). We retrospectively reviewed the medical records of the patients from January 2010 to December 2017. RESULTS: The mean dose to the heart and left anterior descending artery were significantly lower in the DIBH arm (2.10 ± 0.39 and 6.16 ± 0.18 Gy) compared with (4.29 ± 0.60 Gy and 12.69 ± 0.93 Gy, respectively) in the FB arm. The incidence of cardiac events was higher in the FB arm than in the DIBH arm, but it was not statically significant. Our analysis revealed that age, diabetes, hypertension, smoking, mean LAD dose, and heart mean dose were significant prognostic factors for the occurrence of cardiac events in the breath-hold arm. Hypertension, smoking, as well as heart mean dose were independent risk factors for the occurrence of cardiac events. CONCLUSION: Use of the DIBH technique resulted in a significant reduction in doses to the heart, LAD and lesser cardiac events incidence compared to free breathing.

Acute and chronic metabolic effects of carvedilol in high-fructose, high-fat diet-fed mice: implication of ß-arrestin2 pathway.

We aimed to investigate the acute and chronic effects of carvedilol on insulin resistance in high-fructose, high-fat diet (HFrHFD) - fed mice and the implication of the ß-arrestin2 pathway. The acute effect of carvedilol (10 mg/kg, i.p.) on glucose tolerance and hepatic lipid signaling in normal and insulin resistant mice was investigated. Then, the chronic effect of carvedilol on insulin resistance and dyslipidemia in HFrHFD-fed mice was examined. Changes in ß-arrestin2 and its downstream signals in liver, skeletal muscle, and adipose tissue were measured. This involved measuring phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) levels and protein kinase B (AKT) activity. Carvedilol acutely reduced fasting blood glucose levels in both normal and insulin resistant mice without significantly affecting the glucose tolerance. These acute effects were associated with increased hepatic PIP2 but decreased hepatic DAG levels. Chronic administration of carvedilol significantly ameliorated insulin resistance and dyslipidemia in HFrHFD-fed mice. These chronic effects were associated with increased ß-arrestin2, PIP2, and AKT activity levels but decreased DAG levels in the classical insulin target tissues. In conclusion, carvedilol acutely maintains glucose homeostasis and chronically ameliorates insulin resistance and dyslipidemia in HFrHFD-fed mice. The insulin sensitizing effects of carvedilol are highly correlated with the upregulation of ß-arrestin2 pathway.

Propranolol and low-dose isoproterenol ameliorate insulin resistance, enhance ß-arrestin2 signaling, and reduce cardiac remodeling in high-fructose, high-fat diet-fed mice: Comparative study with metformin.

AIMS: ß-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate ß-arrestin2 signaling. The current study examined the effects of the ß-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on ß-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. MATERIALS AND METHODS: Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic ß-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac ß-arrestin2 signaling were then compared among groups. KEY FINDINGS: HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic ß-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac ß-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced ß-arrestin2 signaling with variable efficacies. SIGNIFICANCE: Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating ß-arrestin2 signaling activity. Therefore, ß-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.

Comparison of Long Term Outcomes After Endovascular Treatment Versus Bypass Surgery in Chronic Limb Threatening Ischaemia Patients with Long Femoropopliteal Lesions.

OBJECTIVE: There are currently two treatments available for patients with chronic limb threatening ischaemia (CLTI): open surgical bypass (OSB) and percutaneous transluminal angioplasty with/without stenting (PTA/S). The aim of this study was to compare short and long term outcomes between PTA/S and OSB in CLTI patients with long (GLASS grade III and IV) femoropopliteal disease. METHODS: This was a two centre retrospective study including all consecutive patients with CLTI undergoing first time lower extremity intervention at two distinct vascular surgical centres. Between 1 January 2012 and 1 January 2018, 1 545 CLTI consecutive limbs were treated for femoropopliteal GLASS grade III and IV lesions at two vascular surgical centres. Using covariables from baseline and angiographic characteristics, a propensity score was calculated for each limb. Thus, comparable patient cohorts (235 in PTA/S and 235 in OSB group) were identified for further analysis. The primary outcomes were freedom from re-intervention in the treated extremity and major amputation. Secondary outcomes were all hospital complications among the two patient groups. RESULTS: Total overall complication rates were significantly higher in the OSB group (20.42% vs. 5.96%, p < .001), especially wound infection/seroma rate that required prolonged hospitalisation and further treatment (7.65% vs. 0%, p < .001). After the median follow up of 61 months, re-intervention rates were significantly higher in the PTA/S group (log rank test, 44.68% vs. 29.79%, p = .002), but there was no significant difference in terms of major amputation rates between the two group of patients (log rank test, PTA/S 27.23% vs. OSB 22.13%, p = .17). CONCLUSION: Bypass surgery seems to be superior to PTA/S for GLASS grade III and IV femoropopliteal lesions in patients with CLTI in terms of long term re-intervention rates, but with considerably higher rates of post-operative complications. A larger cohort of patients in currently ongoing randomised trials, as well as prospective cohort studies are necessary to confirm these findings.

The renoprotective effect of glycyrrhizic acid in insulin-resistant rats exposed to aluminum involves the inhibition of TLR4/NF-κB signaling pathway.

Aluminum is well recognized as a nephrotoxic agent. Its hazardous effects arise from the high risk of daily exposure. The consumption of fructose also represents a critical health issue that might negatively impact different organs, including the kidneys. To pursue our previous work, this study aimed to investigate the potential renoprotective effects of glycyrrhizic acid (GLYA) on aluminum-induced nephrotoxicity in insulin-resistant rats. Insulin resistance (IR) was induced by adding fructose (10%) in drinking water for 18 weeks. Male Wistar rats were divided into five groups: control (CTRL), aluminum chloride (ALM, 34 mg/kg/day), fructose (FRCT), aluminum plus fructose (AL/FR), and GLYA (rats received AL/FR and treated with 40 mg/kg GLYA daily). AL/FR resulted in abnormal renal function tests and renal tissue injury. This was associated with increased oxidative stress and inflammation in the renal tissue. Moreover, the expressions of the toll-like receptor 4 (TLR4) and its adaptor proteins were increased in AL/FR group. The administration of GLYA mollified AL/FR-induced renal injury, oxidative stress, activation of the TLR4 signaling pathway, and inflammation. In conclusion, we provide evidence for the promising renoprotective effect of GLYA against AL/FR-induced kidney damage in rats. The renoprotection is attributed to the suppression of oxidative stress and inhibition of the TLR4/NF-κB signaling pathway in the kidneys.

Quercetin and lithium chloride potentiate the protective effects of carvedilol against renal ischemia-reperfusion injury in high-fructose, high-fat diet-fed Swiss albino mice independent of renal lipid signaling.

Renal ischemia-reperfusion injury (R-IRI) is the main cause of acute renal failure. Carvedilol has been shown to protect against R-IRI. However, the underlying mechanisms are still not completely clarified. This study aimed to investigate the role of lipid signaling in mediating carvedilol protective effects against R-IRI in insulin-resistant mice by using two different lipid signaling modulators, quercetin and lithium chloride (LiCl). Mice were fed high-fructose, high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance. At the end of feeding period, mice were randomly distributed into five groups; Sham, R-IRI, Carvedilol (20 mg/kg, i.p.), Carvedilol + Quercetin (10 mg/kg, i.p.), Carvedilol + LiCl (200 mg/kg, i.p.). R-IRI was performed by applying 30 min of unilateral renal ischemia followed by one hour of reperfusion. Quercetin and LiCl were administered 30 min before carvedilol administration and carvedilol was administered 30 min before ischemia. Changes in kidney function tests, histopathology, fibrosis area, lipid signaling, inflammatory, apoptosis and oxidative stress markers in the kidney were measured. Results showed that R-IRI decreased kidney function, impaired renal tissue integrity, modulated lipid signaling and increased renal inflammation, apoptosis and oxidative stress. Carvedilol treatment decreased the detrimental effects induced by R-IRI. In addition, pre-injection of both quercetin and LiCl potentiated the reno-protective effects of carvedilol against R-IRI independent of changes in lipid mediators like phosphatidyl inositol 4,5 bisphosphate (PIP2) and diacylglycerol (DAG). In conclusion, quercetin and LiCl potentiate the protective effects of carvedilol against R-IRI in HFrHFD-fed mice by reducing inflammation and oxidative stress independent of lipid signaling.

Antidepressant activity of anti-hyperglycemic agents in experimental models: A review.

BACKGROUND AND AIMS: Diabetes Mellitus (DM) and depression occur comorbidly and share some pathophysiological mechanisms. The course of depression in patients with the two conditions is severe. Treatment of depression in diabetic patients requires special attention because most of psychopharmacological agents can worsen glycemic control. This article aims to review studies evaluating the antidepressant effect of anti-hyperglycemic agents from preclinical perspective. METHODS: A literature search was performed with PubMed and Google Scholar using relevant keywords (antidiabetic; diabetes; depression; antidepressant; animals) to extract relevant studies evaluating the antidepressant activity of anti-hyperglycemic agents in experimental models. RESULTS: Several studies have reported that some traditional anti-hyperglycemic agents reduce depression-like behavior in the absence or presence of diabetes. These drugs include insulin, glyburide, metformin, pioglitazone, vildagliptin, liraglutide, and exenatide. The antidepressant activity of anti-hyperglycemic agents may be mediated by reducing the blood glucose level, ameliorating the central oxidative stress and inflammation, and regulating the hypothalamic-pituitary-adrenal axis (HPAA). CONCLUSIONS: Drugs which have both antidiabetic and antidepressant activities can provide better treatment strategy for patients with diabetes-associated depression. However, further research studies are still required in human subjects.

Prolonged overnutrition with fructose or fat induces metabolic derangements in rats by disrupting the crosstalk between the hypothalamus and periphery: Possible amelioration with fenofibrate.

Metabolic Syndrome (MetS) increases the risk of developing type 2 diabetes mellitus and cardiovascular complications. The crosstalk between the hypothalamus and periphery is vital for regulating food intake and energy homeostasis. However, it is impaired during MetS. The present study aimed to compare the distinct central and peripheral metabolic derangements induced by a high-fructose drink or high-fat diet, as well as the possible intervention by fenofibrate. Rats were divided into five groups: standard chow diet (SCD) group, high-fructose group (FR), high-fat group (HF), FR plus fenofibrate group (FR-F), and HF plus fenofibrate group (HF-F). FR and HF groups showed hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hyperleptinemia, steatosis, and adipocyte hypertrophy. This was associated with elevated circulating levels of proinflammatory cytokines and free fatty acids (FFAs). The latter mediators are involved in the hypothalamic inflammation and dysregulation of signaling cascades that control food intake and glucose homeostasis. The effects were more pronounced in the HF group than FR group, which were matched with the observed higher levels of plasma FFAs and cytokines. Fenofibrate administration improved not only the peripheral metabolic disturbances, but also the central disturbances associated with insulin resistance induced by FR or HF diet. This study sheds light on the pivotal role of the hypothalamus in diet-induced MetS. Furthermore, the study suggests the utmost importance of developing a standardized model of metabolic syndrome in place of the great diversity between available models, which can induce different effects and negatively impact the validity of prospective studies.

Effect of omega-3 fatty acids on glucose homeostasis: role of free fatty acid receptor 1.

Insulin resistance is a worldwide health problem. This study investigated the acute effects of eicosapentanoic acid (EPA) on glucose homeostasis focusing on the role of free fatty acid receptor 1 (FFAR1) and the chronic effects of fish oil omega-3 fatty acids on insulin resistance. Insulin resistance was induced by feeding mice high-fructose, high-fat diet (HFrHFD) for 16 weeks. In the first part, the acute effects of EPA alone and in combination with GW1100 and DC260126 (FFAR1 blockers) on glucose homeostasis and hepatic phosphatidyl-inositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) were investigated in standard chow diet (SCD)- and HFrHFD-fed mice. In the second part, mice were treated with fish oil omega-3 fatty acids for 4 weeks starting at the week 13 of feeding HFrHFD. Changes in the blood- and liver tissue-insulin resistance markers and FFAR1 downstream signals were recorded at the end of experiment. Results showed that EPA increased 0 and 30 min blood glucose levels after glucose load in SCD-fed mice but improved glucose tolerance in HFrHFD-fed mice. Moreover, FFAR1 blockers reduced EPA effects on glucose tolerance and hepatic PIP2 and DAG levels. On the other hand, chronic use of fish oil omega-3 fatty acids increased FBG levels and decreased serum insulin and triglycerides levels without improving the index of insulin resistance. Also, they increased hepatic ß-arrestin-2, PIP2, and pS473 Akt levels but decreased DAG levels. In conclusion, EPA acutely improved glucose homeostasis in HFrHFD-fed mice by modulating the activity of FFAR1. However, the chronic use of fish oil omega-3 fatty acids did not improve the insulin resistance.

Impact of some oral hypoglycemic agents on type 2 diabetes-associated depression and reserpine-induced depression in rats: the role of brain oxidative stress and inflammation.

Diabetes mellitus and depression are comorbid diseases affecting many patients all over the world. The current study was designed to compare the antidepressant effect of some antidiabetic drugs such as vildagliptin, pioglitazone, glyburide, and metformin on depression-related or unrelated to type 2 diabetes mellitus (T2DM). T2DM was induced by high-fat diet and streptozotocin, while diabetes-unrelated depression was induced by reserpine. Antidiabetic agents reduced diabetes-associated depression as indicated by the reduction in the immobility time in the forced swim test, elevation of cortical and hippocampal serotonin and brain-derived neurotrophic factor (BDNF), and the increase in serum ß-Amyloid 1-42 (Aß1-42) levels. Antidiabetic agents also reduced serum corticosterone levels suggesting their inhibitory effect on hypothalamus-pituitary-adrenal axis activity. The antidepressant activity of the tested compounds was associated with reduction of oxidative stress and inflammation in brain. Vildagliptin showed the highest, while glyburide showed the least antidiabetic and antidepressant activity. Antidepressant activities of pioglitazone and metformin were comparable. The difference in antioxidant and anti-inflammatory activities between groups showed the same pattern of the antidepressant effect suggesting that these two pathways may play role in ameliorating depression in diabetic rats. On the other hand, the administration of reserpine in small doses (0.2 mg/kg) induced depression associated with hyperglycemia in non-diabetic rats. Although all treatments improved glycemic parameters to similar levels, vildagliptin showed the greatest effect on Aß1-42, serotonin, norepinephrine, and BDNF levels. In conclusion, vildagliptin seems to be the leading drug among the tested antidiabetics and may be the most appropriate antidiabetic for managing diabetes-associated depression.

Carvedilol Diminishes Cardiac Remodeling Induced by High-Fructose/High-Fat Diet in Mice via Enhancing Cardiac ß-Arrestin2 Signaling.

BACKGROUND: Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac ß-arrestin2 signaling, and the protective effects of carvedilol as a ß-arrestin-biased agonist. METHODS AND RESULTS: Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, ß-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. CONCLUSION: Carvedilol enhances cardiac ß-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.

The concurrent exposure to aluminium and fructose induces liver injury in rats: Protection by monoammonium glycyrrhizinate.

Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it unavoidable. It is implicated in the aetiology of different neurodegenerative diseases and can induce liver injury. In addition, insulin resistance (IR) plays an essential role in the pathogenesis and the progression of liver disorders. The increased consumption of fructose contained in soft drinks and western pattern diet results in IR that along with the wide distribution of aluminium make the concurrent exposure conceivable and increase the risk of liver injury. Therefore, the present study explores the hepatotoxic effects of aluminium and fructose administered concurrently and evaluates the possible protection by monoammonium glycyrrhizinate (MAG). Liver injury was induced by the administration of aluminium chloride (34 mg/kg/d) plus 10% (w/v) fructose in drinking water. Male rats were treated with either MAG (40 mg/kg/d) or silymarin (SIL, 100 mg/kg/d). The concurrent administration of aluminium and fructose (FRUAL) induced liver injury manifested as a significant elevation of serum liver enzymes activities, bilirubin level, and prothrombin time, as well as reduction of albumin level. On the other hand, the administration of MAG improved the FRUAL-induced aberrations of liver function tests and hepatic cytoarchitecture. We assume that the MAG-induced suppression of oxidative stress, toll-like receptor 4 pathway activation, inflammation, and apoptosis might play a crucial role in the hepatoprotective effect of MAG in this model. Intriguingly, the hepatoprotective effect MAG against FRUAL-induced liver injury surpasses that of the gold standard SIL, suggesting MAG as a better alternative to SIL.

Carvedilol protects against hepatic ischemia/reperfusion injury in high-fructose/high-fat diet-fed mice: Role of G protein-coupled receptor kinase 2 and 5.

Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high-fructose high-fat diet (HFrHFD)-fed mice and the role of G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16 weeks; then mice were subjected to 30 min of ischemia followed by 1 h of reperfusion at the end of feeding period. Carvedilol (20 mg/kg, i.p.) was administered 30 min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10 mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25 mg/kg, i.p.) were administered 30 min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptor downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2 or GRK5 inhibitor did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.

Glycyrrhizic acid and silymarin alleviate the neurotoxic effects of aluminum in rats challenged with fructose-induced insulin resistance: possible role of toll-like receptor 4 pathway.

Aluminum is implicated in the etiology of different neurodegenerative diseases, diabetes and cancer. The current study was conducted to evaluate the protective effects of glycyrrhizic acid (GAM) and silymarin (SLY) on AlCl3-induced neurotoxicity in insulin resistant rats. Insulin resistance (IR) was induced by fructose (10%) in drinking water for 18 weeks. Rats received AlCl3 (34 mg/kg/day) with or without fructose, GAM (40 mg/kg/day), or SLY (100 mg/kg/day). The administration of GAM or SLY suppressed AlCl3-induced memory deficit, oxidative stress, and neuroinflammation in brain tissue of IR rats. Both agents inhibited AlCl3-induced activation of TLR4 signaling pathway including the downstream activation of NF-κB. The results show that IR can partly exacerbate AlCl3-induced neurotoxicity, particularly memory deficit and neuroinflammation. In addition, GAM and SLY showed promising neuroprotective effect against AlCl3-induced brain damage in IR rats. The neuroprotection induced by these natural products might be mediated through their antioxidant and anti-inflammatory effects. The latter effect seems to be mediated via inhibition of TLR4 signaling pathway providing new insights on the mechanisms implicated in AlCl3-induced neurotoxicity and the neuroprotection afforded by GAM and SLY.

Perindopril, fosinopril and losartan inhibited the progression of diethylnitrosamine-induced hepatocellular carcinoma in mice via the inactivation of nuclear transcription factor kappa-B.

Hepatocellular carcinoma (HCC) is a major global health problem. Therapeutic interventions of HCC are still limited because of its complicated molecular pathogenesis. Many reports showed that renin-angiotensin system (RAS) contributes to the development of different types of malignancies. Therefore, the present study aimed to examine the effect of RAS inhibition using perindopril (1 mg/kg), fosinopril (2 mg/kg), or losartan (10 mg/kg) on diethylnitrosamine-induced HCC compared to sorafenib (30 mg/kg). The administration of RAS inhibitors resulted in improved liver function and histologic picture with a reduction in AFP levels. These effects found to be mediated through inactivation of NFкB pathway by the inhibition of NFĸB p65 phosphorylation at the Ser536 residue and inhibition of the phosphorylation-induced degradation of NFĸBia. Consequently, expression levels of cyclin D1 mRNA were significantly lowered. In addition, NFкB-induced TNF-α and TGF-ß1 levels were reduced leading to lower levels of MMP-2 and VEGF. We concluded that RAS inhibition either through inhibiting the ACE or the blockade of AT1R has the same therapeutic benefit and that the tissue affinity of the ACEIs has no impact on its anti-tumor activity. These results suggest that ACEIs and ARBs can serve as promising candidates for further clinical trials in the management of HCC.