Flavoring Agents in E-cigarette Liquids: A Comprehensive Analysis of Multiple Health Risks.

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression.

AIMS: Infiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development. METHODS AND RESULTS: Cell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF. CONCLUSIONS: Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.

Functional and histological assessment of an experimental model of Takotsubo's cardiomyopathy.

BACKGROUND: Our objectives were to characterize functional and structural features of an experimental model of Takotsubo cardiomyopathy, and its response to beta-blockers. METHODS AND RESULTS: In protocol 1, a dose-finding study: 69 rats received various doses of isoproterenol (ISO) and echocardiographic and histologic parameters were measured on days 2 to 3 or day 8. There were no dose-dependent effects and, out of 69 ISO-treated rats, 40 (58.0%) survived and 29 (42.0%) died within 24 hours. Of survivors, 30 had apical akinesis averaging 12.1 ± 1.6% of the long axis LV circumference. Out of the 40 survivors, 32.5% showed apical akinesis ≥ 10%, 42.5% showed akinesis<10% and 25% showed no apical akinesis. The basal portion of the LV was always preserved. At 24 hours, histology and ultrastructure showed necrosis, vacuolization, lipid droplets, mononuclear cell infiltration, damaged mitochondria, and edema. On day 8, apical akinesis fully resolved but histologic abnormalities were still present. In protocol 2, rats were randomized to Control; ISO100 mg/kg; propranolol+ISO; and metoprolol+ISO groups. Pretreatment with propranolol and metoprolol improved survival to 90% and 100% respectively, compared with 60% in the ISO group, but did not reduce the incidence and extent of akinesis or the structural damage. CONCLUSION: TC can be mimicked in a rat model of ISO exposure that demonstrates apical akinesis on days 2 to 3 with full recovery of systolic regional wall motion abnormality despite the presence of persistent foci of necrosis and fibrosis on day 8. Pretreatment with beta-blockers improved survival but did not affect structural and functional alterations.

Combined remote perconditioning and postconditioning failed to attenuate infarct size and contractile dysfunction in a rat model of coronary artery occlusion.

OBJECTIVE: Although preconditioning remains one of the most powerful maneuvers to reduce myocardial infarct size, it is not feasible in the clinical setting to pretreat patients prior to acute myocardial infarction (MI). The purpose of this study was to investigate the effect of more clinically relevant therapies of remote perconditioning, postconditioning, and the combined effect of remote perconditioning and postconditioning on myocardial infarct size in an anesthetized rat model. METHODS: Anesthetized rats were subjected to 45 minutes of proximal left coronary artery occlusion followed by 2 hours of reperfusion. Remote perconditioning was performed 5 minutes after left coronary occlusion with 4 cycles of 5 minutes of occlusion and reperfusion of both the femoral arteries. Postconditioning was applied immediately prior to 2 hours of full reperfusion with 6 cycles of 10 seconds occlusion-reperfusion of the coronary artery. The combined effect was produced by preceding the postconditioning regimen with remote perconditioning, after 5 minutes of left coronary occlusion. RESULTS: Remote perconditioning and postconditioning alone failed to reduce infarct size expressed as percentage of the risk zone (42.2% ± 3.9% and 45.0% ± 4.3%). The combination of remote perconditioning and postconditioning also failed to reduce infarct size (45.3% ± 4.1%) as compared to the untreated ischemia-reperfusion group (48.7% ± 3.4%). Hemodynamics including left ventricular end-systole and end-diastolic pressures, +dP/dt, -dP/dt, and heart rate did not show any improvement in the conditioning groups. CONCLUSION: This study shows that remote perconditioning and postconditioning alone or combined neither improve hemodynamics nor reduce infarct size in the rat model of MI.

Crocus sativus L. (saffron) attenuates isoproterenol-induced myocardial injury via preserving cardiac functions and strengthening antioxidant defense system.

Saffron (dried stigmas of Crocus sativus L.), a naturally derived plant product, has long been used as a traditional ancient medicine against various human diseases. The aim of the series of experiments was to systematically determine whether saffron exerts cardioprotection in isoproterenol-induced myocardial damage. Male Wistar rats (150-175 g) were divided into five groups: control, isoproterenol (ISO) and three saffron (200, 400 and 800 mg/kg) treatment groups. Aqueous extract of saffron or vehicle was administered orally to rats for four weeks. On days 28 and 29, the animals in ISO and saffron treatment groups were administered ISO (85 mg/kg, s.c.) at an interval of 24 h. On day 30, after recording hemodynamics and left ventricular functions, animals were sacrificed for biochemical, histopathological and electromicroscopical examinations. Isoproterenol challenged animals showed depressed hemodynamics and left ventricular functions as evident by decreased left ventricular rate of peak positive and negative pressure change and elevated left ventricular end-diastolic pressure. Structural and ultrastructural studies further confirmed the damage which was reconfirmed by increased thiobarbituric acid reactive substances (p<0.001) and decreased creatine kinase-MB and lactate dehydrogenase (p<0.001). In addition, significant reduction in superoxide dismutase and catalase (p<0.001) was observed in ISO group. Our results suggested that saffron at all the doses exerted significant cardioprotective effect by preserving hemodynamics and left ventricular functions, maintaining structural integrity and augmenting antioxidant status. Among the different doses used, saffron at 400mg/kg dose exhibited maximum protective effects which could be due to maintenance of the redox status of the cell reinforcing its role as an antioxidant.

Curcumin protects rat myocardium against isoproterenol-induced ischemic injury: attenuation of ventricular dysfunction through increased expression of Hsp27 along with strengthening antioxidant defense system.

This investigation examines the role of heat shock protein (Hsp) 27 and its modulation by curcumin in isoproterenol-induced myocardial ischemic injury in rats. Evidence from hemodynamic functions and oxidative stress parameters were also included in the study. The animals were divided into control, isoproterenol, and curcumin 100, 200, and 400 mg/kg treatment groups. Curcumin was administered orally for 15 days to all the treated groups. On 13th and 14th day, isoproterenol (85 mg/kg, s.c.) was injected to curcumin-treated and isoproterenol group. On day 15, hemodynamic parameters were recorded. Thereafter, animals were sacrificed and hearts were kept for biochemical and Western blot analysis. We found dose-dependent increase in the expression of Hsp27 with drastic fall at highest dose. Hemodynamically, the lower 2 doses also restored the cardiac function as evident by improved contractile functions, decreased left ventricular end-diastolic pressure, restored arterial pressures, and heart rate. In addition, there was an increase in then level of superoxide dismutase, catalase, reduced glutathione, and decreased production of thiobarbituric acid reactive substances and leakage of cardiac necroenzyme creatine kinase-MB isoenzyme and lactate dehydrogenase in curcumin 100 and 200 mg/kg group as compared with isoproterenol. However, at a dose of 400 mg/kg, there was ineffectual protection against isoproterenol-induced myocardial damage. Our results suggested 200 mg/mg as the most optimum therapeutic dose showing improved cardiac function due to stabilization of cytoskeleton structure which in turn is attributed to Hsp27 expression along with fortified antioxidant defense system.

Dose-dependent actions of curcumin in experimentally induced myocardial necrosis: a biochemical, histopathological, and electron microscopic evidence.

Curcumin, an active component of turmeric, is a well-known antioxidant due to its reactive oxygen species (ROS) scavenging property. However, some in vitro studies have suggested that curcumin induces generation of ROS at higher doses and thus exerts pro-oxidant effect. We demonstrate, for the first time, the dose-dependent effects of curcumin in isoprenaline-induced model of myocardial necrosis in rats. The animals were assigned to control, isoprenaline and three curcumin treatment groups. Curcumin (100, 200, and 400 mg/kg) and vehicle (dimethyl sulfoxide) were administrated orally for 15 days and isoprenaline (85 mg/kg, s.c.) was given to curcumin treated and isoprenaline group on 13th and 14th day, respectively. Thereafter, on 15th day, the animals were sacrificed for biochemical analysis along with histopathological and ultrastructural examination. There was an increase in glutathione, superoxide dismutase (SOD), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) levels, decrease in thiobarbituric acid reactive substances (TBARS), and preservation of myocardial architecture in the curcumin (100 and 200 mg/kg) treated groups. However, at 400 mg/kg dose there was ineffectual protection against isoprenaline-induced myocardial damage. Instead, there was significant lipid peroxidation as evident by increased levels of TBARS (93.87 +/- 9.93, p < 0.0001) and decrease in CK-MB (206.32 +/- 13.54, p < 0.0001) and LDH (134.26 +/- 9.13, p < 0.01) as compared to the two lower doses. Hence, it can be concluded that curcumin augments endogenous antioxidant system at lower doses but mediates ROS induction at higher concentration leading to myocardial damage.