Angiotensin II constricts mouse iliac arteries: possible mechanism for aortic aneurysms.

Abdominal aortic aneurysms (AAA) result from maladaptive remodeling of the vascular wall and reduces structural integrity. Angiotensin II (AngII) infusion has become a standard laboratory model for studying AAA initiation and progression. We determined the different vasoactive responses of various mouse arteries to Ang II. Ex vivo isometric tension analysis was conducted on 18-week-old male C57BL/6 mice (n = 4) brachiocephalic arteries (BC), iliac arteries (IL), and abdominal (AA) and thoracic aorta (TA). Arterial rings were mounted between organ hooks, gently stretched and an AngII dose response was performed. Rings were placed in 4% paraformaldehyde for immunohistochemistry analysis to quantify peptide expression of angiotensin type 1 (AT1R) and 2 receptors (AT2R) in the endothelium, media, and adventitia. Results from this study demonstrated vasoconstriction responses in IL were significantly higher at all AngII doses when compared to BC, and TA and AA responses (maximum constriction-IL: 68.64 ± 5.47% vs. BC: 1.96 ± 1.00%; TA: 3.13 ± 0.16% and AA: 2.75 ± 1.77%, p < 0.0001). Expression of AT1R was highest in the endothelium of IL (p < 0.05) and in the media and (p < 0.05) adventitia (p < 0.05) of AA. In contrast, AT2R expression was highest in endothelium (p < 0.05), media (p < 0.01, p < 0.05) and adventitia of TA. These results suggest that mouse arteries display different vasoactive responses to AngII, and the exaggerated response in IL arteries may play a role during AAA development.

Cisplatin treatment reduces contraction to angiotensin II by altering expression of angiotensin II receptors: a pilot study.

The renin angiotensin system is a key regulator of blood pressure homeostasis. Angiotensin type 1 (AT1R) and 2 receptors (AT2R) have been investigated as targets for cisplatin-induced acute kidney injury; however, their therapeutic potential remains inconclusive. This pilot study aimed to determined the effect that acute cisplatin treatment had on angiotensin II (AngII)-induced contraction in blood vessels and expression profiles of AT1R and AT2R in mouse arteries and kidneys. Male C57BL/6 mice at 18 week of age (n = 8) were treated with vehicle or bolus dose of cisplatin (12.5 mg/kg). Thoracic aorta (TA), adnominal aorta (AA), brachiocephalic arteries (BC), iliac arteries (IL) and kidneys were collected for isometric tension and immunohistochemistry analysis. Cisplatin treatment reduced IL contraction to AngII at all doses (p < 0.01, p < 0.001, p < 0.0001); however, AngII did not induce contraction in TA, AA or BC in either treatment group. Following cisplatin treatment, AT1R expression was significantly upregulated in the media of TA (p < 0.0001) and AA (p < 0.0001), and in the endothelium (p < 0.05) media (p < 0.0001) and adventitia (p < 0.01) of IL. Cisplatin treatment significantly reduced AT2R expression in the endothelium (p < 0.05) and media (p < 0.05) of TA. In renal tubules, both AT1R (p < 0.01) and AT2R (p < 0.05) were increased following cisplatin treatment. Herein, we report that cisplatin reduces AngII-mediated contraction in IL and may be explained by an absence of normal counterregulatory expression of AT1R and AT2R, indicating other factors are involved.

Procalcitonin kinetics following abdominal aortic surgery and its value for postoperative intestinal ischaemia detection.

OBJECTIVE: The purpose of our study was to describe perioperative kinetics of procalcitonin (PCT) in patients undergoing aortic surgery, to compare the kinetics in the open abdominal aortic aneurysm (AAA) repair and aortobifemoral bypass for aortoiliac occlusive disease (AIOD), and to evaluate the ability of PCT to detect intestinal ischaemia. METHODS: A prospective non-randomized observational cohort study in 80 patients (62 men and 18 women) undergoing elective aortic surgery was performed. Serum PCT was measured at baseline and defined intraoperative and postoperative timepoints up to postoperative day 7. MRI contrast-enhanced imaging was used to detect intestinal ischaemia. RESULTS: The comparison of the AAA and AIOD cohort did not show any significant difference in PCT levels. Patients with intestinal ischaemia had higher serum PCT at multiple timepoints postoperatively. The most accurate timepoints for early diagnosis were postoperative day 3, followed by 24 h after declamping of the vascular reconstruction, and postoperative day 7. The sensitivity and negative predictive values were 100% in all mentioned timepoints. However, event at the best timepoint the specificity was 89% and the positive predictive value 43%. CONCLUSIONS: Procalcitonin levels in the postoperative period at proper timepoints might help to detect postoperative intestinal ischaemia. The limitation of this marker is its low specificity for intestinal ischaemia and low positive predictive value. The highest value of this marker is that it can rule out this complication because normal PCT levels mean that intestinal ischaemia is very unlikely.

Higher Levels of Serum Ionic Calcium are Associated with Macular Edema in Patients with Diabetic Retinopathy.

BACKGROUND: The aim was to study the association of serum total calcium, ionic calcium, and magnesium with increases in macular thickness parameters and photoreceptor ellipsoid zone (EZ) disruption in diabetic macular edema (DME). METHODS: This study is a tertiary care center based observational cross-sectional study with sixty-six consecutive cases, divided into 3 groups of 22 cases each with no diabetic retinopathy (No DR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) and a control group of 22 healthy controls. Best corrected visual acuity (BCVA) was measured on logMAR scale. Central subfield thickness (CST), cube average thickness (CAT), and EZ disruption were assessed using spectral-domain optical coherence tomography (SD-OCT). Serum total calcium, ionic calcium, and magnesium were measured using standard protocol. Data was analyzed statistically. RESULTS: Significant correlation was found between the increase in CST and the increase in serum total calcium and serum ionic calcium. Increase in CAT was significantly correlated with an increase in serum total calcium, serum ionic calcium, and a decrease in serum magnesium. Grades of EZ disruption and logMAR BCVA were also found to be significantly positively associated with serum total calcium and ionic calcium and negatively with serum magnesium. CONCLUSIONS: Increased levels of serum ionic calcium and decreased levels of serum magnesium are associated with an increase in macular thickness and EZ disruption in DME.

Kinetics of platelet adhesion to a fibrinogen-coated surface in whole blood under flow conditions.

AIM: To test a novel method of assessment of platelet adhesion to a fibrinogen-coated surface in whole blood under flow conditions. METHODS: We developed a fluidic device that mimics blood flow in vessels. The method of detection of platelet adhesion is based on recording of a scattered laser light signal from a fibrinogen-covered surface. Testing was performed in platelet-rich plasma (PRP) and whole blood of healthy volunteers. Control measurements were performed, followed by tests with inhibition of platelet GPIIa/IIIb and GPIb receptors. Then, the same testing sequence was performed in whole blood of persons with autoimmune thrombocytopenia and type 3 von Willebrand disease. RESULTS: The change in intensity of scattered light was 2.7 (2.4; 4.1) times higher in whole blood (0.2 ± 0.08V, n = 7) than in PRP (0.05 ± 0.02 V, n = 7), p < 0.01. The blocking of GP IIb/IIIa receptors decreased the intensity of scattered light to 8.5 (6.5;12)%; the blocking of GPIb receptors decreased it to 34 (23;58)%, p < 0.01. In the whole blood of a person with autoimmune thrombocytopenia, the inhibition of GPIb receptors decreased platelet adhesion, but no effect was observed in type 3 von Willebrand disease. Inhibition of platelet GPIIb/IIIa receptors alone or combined inhibition of GPIb and GPIIb/IIIa receptors resulted in almost total suppression of adhesion in both cases. CONCLUSION: Our system effectively registers platelet adhesion to a fibrinogen-coated surface under controlled-flow conditions and may successfully be applied to the investigation of platelet adhesion kinetics.

Imipridone enhances vascular relaxation via FOXO1 pathway.

Cardiovascular complications are a side effect of cancer therapy, potentially through reduced blood vessel function. ONC201 (TIC10) is currently used in phase 2 clinical trials to treat high-grade gliomas. TIC10 is a phosphatidylinositol 3-kinase (PI3K)/AKT/extracellular signal-regulated kinase (ERK) inhibitor that induces apoptosis via upregulation of TNF-related apoptosis-inducing ligand, which via stimulation of FOXO and death receptor could increase eNOS upregulation. This has the potential to improve vascular function through increased NO bioavailability. Our aim was to investigate the role of TIC10 on vascular function to determine if it would affect the risk of CVD. Excised abdominal aorta from White New Zealand male rabbits were cut into rings. Vessels were incubated with TIC10 and AS1842856 (FOXO1 inhibitor) followed by cumulative doses of acetylcholine (Ach) to assess vessel function. Vessels were then processed for immunohistochemistry. Incubation of blood vessels with TIC10 resulted in enhanced vasodilatory capacity. Combination treatment with the FOXO1 inhibitor and TIC10 resulted in reduced vascular function compared to control. Immunohistochemical analysis indicated a 3-fold increase in death receptor 5 (DR5) expression in the TIC10-treated blood vessels but the addition of the FOXO1 inhibitor downregulated DR5 expression. The expression of DR4 receptor was not significantly increased in the presence of TIC10; however, addition of the FOXO1 inhibitor downregulated expression. TIC10 has the capacity to improve the function of healthy vessels when stimulated with the vasodilator Ach. This highlights its therapeutic potential not only in cancer treatment without cardiovascular side effects, but also as a possible drug to treat established CVD.

The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases.

The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin-converting enzyme (ACE) comprises the classical RAS. The non-classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1-7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non-classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

The therapeutic effect of B-type natriuretic peptides in acute decompensated heart failure.

B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.

The effect of Betanin parenteral pretreatment on Jejunal and pulmonary tissue histological architecture and inflammatory response after Jejunal ischemia-reperfusion injury.

Intestinal ischemic-reperfusion (IR) injury has detrimental effects on both local and distant organs in the body. Betanin is known for its antioxidant properties, and it is found mostly in vegetables. Therefore, the aim of the present study was to test the hypothesis that betanin administration prior intestinal IR, may be beneficial in protecting jejunal mucosa and lung parenchyma against IR damage. Male specific pathogen-free Charles River Wistar rats were used (n = 42). Betanin (50 mg/kg) was administered intraperitoneally 30 min before ischemia of the superior mesenteric artery lasting 1 h, followed by 1, 4 and 24 h of reperfusion. Immunohistochemical as well as histomorphometrical analysis indicated a protective effect of betanin pretreatment on jejunal tissue. Regarding morphometrical analysis betanin significantly (p < 0.01) augments intestinal villus height after 24 of reperfusion comparing to early stages. Betanin application reduced number of mast cells population in early reperfusion periods (p < 0.05). The protective effect of betanin on lung parenchyma, was detected in late reperfusion period (24 h) with improvement of histopathological injury index and morphometric analysis (p < 0.001 for both). The improvement of histopathological injury index (p < 0.001) and morphometric analysis (p < 0.001) during the late reperfusion period, suggests a protective effect of betanin on lung parenchyma. Moreover, suppression of the inflammatory response was mirrored by the reduction of myeloperoxidase (MPO) positive cells within lung parenchyma after 1 and 4 h of reperfusion (p < 0.001). Especially, during the first 4 h of reperfusion after betanin administration, a reduction of 74% of the polymorphonuclear neutrophils infiltration (MPO positive cell population) and of a nearly 46% of active MCs was observed. Upon morphometric examination, the lung histological architecture after 24 h of reperfusion appeared to be almost 100% better following betanin treatment, with 25% thinner interalveolar septa and 20% larger alveolar surface for respiratory gas exchange. The results suggest that betanin pretreatment protects the jejunal mucosa and the lung parenchyma, as well as reduces the inflammatory cell density after intestinal IR injury.

Impact of drugs on venous thromboembolism risk in surgical patients.

PURPOSE: This review focuses on the most common drugs administered to surgical patients during the perioperative period that affect the risk of venous thromboembolism (VTE). RESULTS: Among analgesics, the risk of VTE is increased in patients treated with diclofenac, ibuprofen, and rofecoxib, but not naproxen, while metamizole can confer a protective effect. The relationship between sedatives and VTE has not been sufficiently studied. Tricyclic antidepressants, low-potency serotonin reuptake inhibitors, and antipsychotics have been associated with increased risk of VTE. The use of diuretics in the perioperative period is poorly researched; however, hyponatremia is considered a risk factor. Other factors that may influence the risk of VTE include bridging anticoagulation, allogeneic transfusion, and hemostatic management before surgery. Pharmacotherapy for HIV or cancer may also increase VTE risk. CONCLUSION: Increased monitoring for VTE is therefore advisable in surgical patients and those receiving antipsychotics, antidepressants, diuretics, or analgesics.

Putative Nox2 inhibitors worsen homocysteine-induced impaired acetylcholine-mediated relaxation.

BACKGROUND AND AIM: Increased homocysteine (Hcy) is associated with coronary artery disease (CAD). Hcy increases reactive oxygen species (ROS) via NADPH oxidases (Nox), reducing acetylcholine-mediated vasorelaxation. We aimed to determine if putative Nox2 inhibitors prevent Hcy-impaired acetylcholine-mediated vasorelaxation. METHODS AND RESULTS: New Zealand White rabbit and wild-type (C57BL/6) and Nox2-/- (NOX) mice aortic rings were mounted in organ baths. Rabbit rings were incubated with either apocynin (10 µM), gp91ds-tat (GP, 1 µM) or PhoxI2 (1 µM) and mice rings GP (1 µM) only. Some rabbit rings were incubated with 3 mM Hcy, before pre-contraction, followed by dose-response relaxation to acetylcholine (ACh; 0.01µM-10µM). In rabbit rings treated with Hcy and GP, O2‾ donor pyrogallol (1 µM) or Akt activator SC79 (1 µM) was added 5 min before ACh. Mice rings were used to compare Nox2 deletion to normal acetylcholine-mediated relaxation. In rabbits, Hcy reduced acetylcholine-mediated relaxation vs. control (p < 0.0001). Treatment + Hcy reduced relaxation compared with treatment alone (p < 0.0001). Pyrogallol and SC79 reversed the response of GP + Hcy (p = 0.0001). In mice, Nox2 deletion reduced acetylcholine-mediated vasorelaxation. Rabbit tissue analysis revealed that Hcy reduced eNOS phosphorylation at Thr495 and increased eNOS phosphorylation at Ser1177; no further alteration at Thr495 was observed with GP. In contrast, GP prevented increased phosphorylation at Ser1177. CONCLUSIONS: Apocynin, GP and PhoxI2 worsens acetylcholine-mediated vascular relaxation in rabbit aorta, which is supported by results from mouse Nox2 deletion data. These inhibitors worsen Hcy-induced vascular dysfunction, suggesting that current putative Nox2 inhibitors might not be useful in treating HHcy.

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection.

Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+-signaling and loss of [Ca2+]i homeostasis contributes to tumor initiation proliferation, angiogenesis, and other key processes that support tumor progression in several different cancers. Currently, chemically and functionally distinct drugs are used as chemotherapeutic agents in the treatment and management of cancer among which certain anti-cancer drugs reportedly suppress pro-survival signals and activate pro-apoptotic signaling through modulation of Ca2+-signaling-dependent mechanisms. Most importantly, the modulation of [Ca2+]i levels via the endoplasmic reticulum-mitochondrial axis and corresponding action of channels and pumps within the plasma membrane play an important role in the survival and death of cancer cells. The endoplasmic reticulum-mitochondrial axis is of prime importance when considering Ca2+-signaling-dependent anti-cancer drug targets. This review discusses how calcium signaling is targeted by anti-cancer drugs and highlights the role of calcium signaling in epigenetic modification and the Warburg effect in tumorigenesis.

Markers of Atherosclerosis: Part 2 - Genetic and Imaging Markers.

This is Part 2 of a two-part review summarising current knowledge on biomarkers of atherosclerosis. Part 1 addressed serological biomarkers. Here, in part 2 we address genetic and imaging markers, and other developments in predicting risk. Further improvements in risk stratification are expected with the addition of genetic risk scores. In addition to single nucleotide polymorphisms (SNPs), recent advances in epigenetics offer DNA methylation profiles, histone chemical modifications, and micro-RNAs as other promising indicators of atherosclerosis. Imaging biomarkers are better studied and already have a higher degree of clinical applicability in cardiovascular (CV) event prediction and detection of preclinical atherosclerosis. With new methodologies, such as proteomics and metabolomics, discoveries of new clinically applicable biomarkers are expected.

Markers of Atherosclerosis: Part 1 - Serological Markers.

Atherosclerosis is a major contributor to morbidity and mortality worldwide. With therapeutic consequences in mind, several risk scores are being used to differentiate individuals with low, intermediate or high cardiovascular (CV) event risk. The most appropriate management of intermediate risk individuals is still not known, therefore, novel biomarkers are being sought to help re-stratify them as low or high risk. This narrative review is presented in two parts. Here, in Part 1, we summarise current knowledge on serum (serological) biomarkers of atherosclerosis. Among novel biomarkers, high sensitivity C-reactive protein (hsCRP) has emerged as the most promising in chronic situations, others need further clinical studies. However, it seems that a combination of serum biomarkers offers more to risk stratification than either biomarker alone. In Part 2, we address genetic and imaging markers of atherosclerosis, as well as other developments relevant to risk prediction.

Hyperglycemia potentiates the effect of ionic calcium in photoreceptor ellipsoid zone disruption in diabetic retinopathy.

PURPOSE: To study the association of serum ionic calcium and glycated hemoglobin (HbA1c) with retinal photoreceptor ellipsoid zone (EZ) disruption in diabetic retinopathy (DR). METHODS: This is a tertiary care center-based observational cross-sectional study. Sixty-three consecutive cases, divided into 21 cases each with no diabetic retinopathy, non-proliferative diabetic retinopathy and proliferative diabetic retinopathy were included. Twenty-one healthy controls were also included. Ellipsoid zone disruption was assessed using spectral-domain optical coherence tomography. Serum ionic calcium and HbA1c were measured using standard protocol. Patient data from cases were divided into two groups according to their HbA1c levels: group 1 (HbA1c < 7, n = 26) and group 2 (HbA1c > 7, n = 37). Data were analyzed statistically. RESULTS: Mean ionic calcium levels in group 1 and group 2 were 1.131 ± 0.073 mmol/dL and 1.170 ± 0.070 mmol/dL, respectively. In group 1, 11 out of 26 had EZ disruption (42.3%). Similarly, in group 2, 29 out of 37 had EZ disruption (78.4%). On logistic regression analysis, as compared to group 1, ellipsoid zone disruption was found to be positively associated with serum ionic calcium (p = 0.01) in group 2 cases. CONCLUSION: Increased levels of serum ionic calcium are associated with increased EZ disruption in patients with HbA1c > 7 in DR.

Transthoracic Coronary Flow Data at Rest Predict High-Risk Stress Tests.

Background Several recent studies have reported the opportunity to diagnose significant narrowing of the coronary arteries without stress testing using local flow acceleration. Purpose To define how often patients with increased coronary flow velocities at rest (≥ 0.70 m/s) have a positive exercise echocardiography test. Material and Methods A total of 150 patients scheduled for exercise echocardiography were studied using transthoracic Doppler echocardiography in order to assess coronary artery flow velocity before exercise. Pulsed wave Doppler registered blood flow velocity placed on the color signal. The maximal diastolic velocity of coronary flow was measured. Results Of participants, 16% had a velocity of more than 0.70 m/s in the left main/proximal left anterior/proximal left circumflex arteries (LM/pLAD). A significant correlation was observed between the value of the maximal velocity in LM/pLAD and the ejection fraction at the peak of exercise ( r ≈ -0.39, P < 0.0001); between the value of the maximal velocity in LM/pLAD and index of wall motion abnormalities (IWMA) at the peak of exercise ( r ≈ 0.44, P < 0.0001); and between the value of the maximal velocity in LM/pLAD and dIWMA ( r ≈ 0.41, P < 0.0001). Afterwards, severe ischemia in stress echocardiography tests was observed in this group. The average IWMA of these tests was found to be 2.3. Sixty-two angiograms were available for comparison with Doppler data. Conclusion There is a significant correlation between the value of the maximal velocity in LM/pLAD/pLCx at rest and the severity of wall motion abnormalities during exercise tests.

Time to redefine body mass index categories in chronic diseases? Spotlight on obesity paradox.

Obesity is a complex condition classically characterised by excessive body fat accumulation and represents one of the most important public health problems worldwide. Although several epidemiological studies have shown that elevated BMI is associated with higher morbidity, and with increased rate of death from all causes and from cardiovascular disease, accumulating evidence suggests that being overweight or obese may be protective (the so-called obesity paradox), at least in chronic diseases. These observations, not only question the validity of the BMI system, but also raise the intriguing question of whether we should redefine what the normal range of BMI is in individuals suffering from a chronic disease. In the present article, we review the available information on the association between elevated BMI and increased morbidity and mortality including obesity-related paradoxes, explore key aspects of the role and limitations of BMI as a measure of increased adiposity and outline potential solutions to address the current controversies regarding the impact of obesity on human health.

Antineoplastic effects of clove buds (Syzygium aromaticum L.) in the model of breast carcinoma.

It is supposed that plant functional foods, rich in phytochemicals, may potentially have preventive effects in carcinogenesis. In this study, the anticancer effects of cloves in the in vivo and in vitro mammary carcinoma model were assessed. Dried flower buds of cloves (CLOs) were used at two concentrations of 0.1% and 1% through diet during 13 weeks after the application of chemocarcinogen. After autopsy, histopathological and immunohistochemical analyses of rat mammary carcinomas were performed. Moreover, in vitro evaluation using MCF-7 cells was carried out. Dietary administered CLO caused the dose-dependent decrease in tumour frequency by 47.5% and 58.5% when compared to control. Analysis of carcinoma cells in animals showed bcl-2, Ki67, VEGFA, CD24 and CD44 expression decrease and Bax, caspase-3 and ALDH1 expression increase after high-dose CLO administration. MDA levels were substantially decreased in rat carcinomas in both CLO groups. The evaluation of histone modifications revealed increase in lysine trimethylations and acetylations (H4K20me3, H4K16ac) in carcinomas after CLO administration. TIMP3 promoter methylation levels of CpG3, CpG4, CpG5 islands were altered in treated cancer cells. An increase in total RASSF1A promoter methylation (three CpG sites) in CLO 1 group was found. In vitro studies showed antiproliferative and pro-apoptotic effects of CLO extract in MCF-7 cells (analyses of cytotoxicity, Brdu, cell cycle, annexin V/PI, caspase-7, Bcl-2 and mitochondrial membrane potential). This study showed a significant anticancer effect of clove buds in the mammary carcinoma model in vivo and in vitro.

Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases.

Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. Stem Cells 2016;34:1474-1486.

Downregulation of myogenic microRNAs in sub-chronic but not in sub-acute model of daunorubicin-induced cardiomyopathy.

Cardiac muscle-related microRNAs play important roles in cardiac development and disease by translational silencing of mRNAs, the dominant mechanism of microRNA action. To test whether they could be involved in daunorubicin-associated cardiomyopathy (DACM), we determined expression patterns of myomiRs in two distinct models of DACM. We used 10-12 weeks old male Wistar rats. In the sub-acute model, rats were administered with six doses of daunorubicin (DAU-A, 3 mg/kg, i.p., every 48 h). Rats were sacrificed two days after the last dose. In the sub-chronic model, anaesthetized rats were administered a single dose of daunorubicin (15 mg/kg, i.v., DAU-C). Age-matched controls (CON) received vehicle. Rats were sacrificed eight weeks later. Left ventricular (LV) functions (LV pressure, rate of pressure development, +dP/dt and decline, -dP/dt) were measured using left ventricular catheterization. Expressions of myomiRs (miR-208a, miR-499, miR-1 and miR-133a), markers of cardiac failure (atrial and brain natriuretic peptides genes; Nppa and Nppb) and myosin heavy chain genes (Myh6, Myh7, Myh7b) in cardiac tissue were determined by RT-PCR. Protein expression of gp91phox NADPH oxidase subunit was detected by immunoblotting. Both DAU groups exhibited a similar depression of LV function, and LV weight reduction, accompanied by an upregulation of natriuretic peptides, and a decrease of Myh6 to total Myh ratio (-18% in DAU-A and - 25% in DAU-C, as compared to controls; both P < 0.05). DAU-C, but not DAU-A rats had a 35% mortality rate and exhibited a significantly increased gp91phox expression (DAU-C: 197 ± 33 versus CON-C: 100 ± 11; P < 0.05). Interestingly, myomiRs levels were only reduced in DAU-C compared to CON-C (miR-208: -45%, miR-499: -30%, miR-1: -29%, miR- and miR133a: -25%; all P < 0.05) but were unaltered in DAU-A. The lack of myomiRs expression, particularly in sub-chronic model, suggests the loss of control of myomiRs network on late progression of DACM. We suppose that the poor inhibition of mRNA targets might contribute to chronic DACM.