Pathway to environmental sustainability: Assessing the role of productive capacity, remittances, and uncertainty in sub-Saharan Africa.

Unlike previous studies that have examined the association between different economic development parameters and environmental sustainability, the present study utilised an index of productive capacity to offer an in-depth understanding of the ecological impact of improving a nation's productive resources. It also emphasised the importance of remittances in reducing environmental degradation in uncertain economic and political environments. This study applied the system GMM technique and an advanced panel quantile regression technique to 36 Sub-Saharan Africa (SSA) region countries from 2000 to 2022. The findings showed that improvements in productive capacity might exert pressure on environmental quality, uncertainty, and the inflow of remittances, which tended to have a positive effect, ultimately leading to better environmental outcomes. Furthermore, the study indicated that these variables' impacts differed depending on each country's prevailing ecological conditions. It is, therefore, vital that efforts to achieve sustainable development in the SSA region consider the combined impact of these factors on environmental quality.

Ethanol-induced lung and cardiac right ventricular inflammation and remodeling underlie progression to pulmonary arterial hypertension.

BACKGROUND: Current research on ethanol-induced cardiovascular anomalies has focused on left ventricular (LV) function and blood pressure. To extend this area of research, we sought to determine whether ethanol-induced alterations in the structure and function of the right cardiac ventricle (RV) and pulmonary artery (PA) lead to pulmonary arterial hypertension (PAH). METHODS: Two groups of male Sprague-Dawley rats received a balanced liquid diet containing 5% ethanol (w/v) or a pair-fed isocaloric liquid diet for 8 weeks. Weekly echocardiography was conducted to evaluate cardiopulmonary function, and lung and RV tissues were collected for ex vivo histological and molecular studies. RESULTS: The ethanol-treated rats exhibited: (1) Elevated mean pulmonary arterial pressure and decreased pulmonary artery acceleration time/ejection time; (2) Pulmonary vascular remodeling comprising intrapulmonary artery medial layer thickening; and (3) RV hypertrophy along with increased RV/LV + septum, RV diameter, RV cardiomyocyte cross-sectional area, and LV mass/body weight ratio. These responses were associated with increased lung and RV pro-inflammatory markers, endothelin-1 (ET-1), TNF-α, and IL-6 levels and higher ET-1, ET-1 type A/B receptor ratio, and downregulation of the cytoprotective protein, bone morphogenetic protein receptor 2 (BMPR2), in the lungs. CONCLUSION: These findings show that moderate ethanol-induced cardiopulmonary changes underlie progression to PAH via an upregulated proinflammatory ET1-TNFα-IL6 pathway and suppression of the anti-inflammatory BMPR2.

Comparative Study Between Single Layer and Double Layer Graft Technique in Tympanoplasty for Subtotal Tympanic Membrane Perforation.

Introduction Tympanoplasty is the main treatment of mucosal type of chronic suppurative otitis media. Objective The aim of the present study was to compare clinical outcomes in terms of healing and audiological outcomes of two groups. The authors used single layer graft (perichondrium with cartilage island) graft in one group and double layer grafts (perichondrium cartilage island composite plus temporalis fascia) were used in the second group. Methods Forty patients complained of chronic suppurative otitis media safe type with subtotal perforation subdivided into two groups. The first group author used single-layer perichondrium with cartilage island graft (composite graft) while in the second group authors used double graft in the form of perichondrium/cartilage island (composite graft) plus temporalis fascia. Results There was no significant difference in the mean Air bone gap (ABG) between pre- and post-operative audiometry in subjects who had single layer tympanoplasty. There was a significant difference in the mean ABG between pre- and postoperative audiometry in subjects who had double layer tympanoplasty. There was a significant difference in in the mean ABG differences between subjects who had single layer tympanoplasty and double layer tympanoplasty. Also, there was a significant difference in the healing of the tympanic membrane between subjects who had single layer tympanoplasty and double layer tympanoplasty. Conclusion Tympanoplasty by double graft (temporalis fascia and tragal cartilage/perichondrium) achieved a considerable improvement in healing of the tympanic membrane ™ with lower risk for residual perforation or graft rejection.

Estrogen-mediated mitigation of cardiac oxidative stress in ovariectomized rats is associated with upregulated cardiac circadian clock Per2 and heart-specific miRNAs.

AIM: Estrogen (E2) confers cardioprotection in premenopausal women and in models of menopause and its effects, mostly studied in female reproductive organs, vary on a circadian rhythm basis in relation to the circadian clock genes. However, it remains unknown if a similar circadian pattern exists in the female heart in a manner that explains, at least partly, the cardioprotective effect of E2. The aim of the present investigation was to determine if upregulation of the circadian clock Per2 and its regulated heart-specific miRNAs, and redox enzymes contribute to the E2-mediated cardioprotection in ovariectomized rats. MAIN METHODS: Rats were subjected to ovariectomy (OVX) 2-weeks prior to a 2-week E2 treatment. On the last treatment day, hearts were collected every 4 h. for ex-vivo biochemical measurements. In parallel studies, telemetric mean arterial pressure (MAP) was obtained at the tissue collection times. KEY FINDINGS: OVX + E2 rats exhibited lower body weight during daytime and MAP during day and night times, and their hearts exhibited: (1) higher Per2 protein abundance, cardioprotective miRNAs (miRNA1, miRNA133a, miRNA208a, miRNA499), mALDH2, and catalase; (2) lower reactive oxygen species, cardio-detrimental miRNA652, carbonyl, MDA and HO-1 levels. The reciprocal Per2/HO-1 relationship was more evident during the daytime and correlated with the upregulated cardioprotective miRNAs in OVX + E2 rats. Finally, cardiac Per2, heart-specific miRNAs and reactive oxygen species levels and redox enzymes activities were similar in normal female and OVX + E2 rats. SIGNIFICANCE: Enhancement of cardiac Per2, redox enzymes and heart-specific miRNAs likely contribute to E2-mediated mitigation of cardiac oxidative stress in OVX rats.

Comparative Study Between Single Layer and Double Layer Graft Technique in Tympanoplasty for Subtotal Tympanic Membrane Perforation

Abstract Introduction Tympanoplasty is the main treatment of mucosal type of chronic suppurative otitis media. Objective The aim of the present study was to compare clinical outcomes in terms of healing and audiological outcomes of two groups. The authors used single layer graft (perichondrium with cartilage island) graft in one group and double layer grafts (perichondrium cartilage island composite plus temporalis fascia) were used in the second group. Methods Forty patients complained of chronic suppurative otitis media safe type with subtotal perforation subdivided into two groups. The first group author used single-layer perichondrium with cartilage island graft (composite graft) while in the second group authors used double graft in the form of perichondrium/cartilage island (composite graft) plus temporalis fascia. Results There was no significant difference in the mean Air bone gap (ABG) between pre- and post-operative audiometry in subjects who had single layer tympanoplasty. There was a significant difference in the mean ABG between pre- and postoperative audiometry in subjects who had double layer tympanoplasty. There was a significant difference in in the mean ABG differences between subjects who had single layer tympanoplasty and double layer tympanoplasty. Also, there was a significant difference in the healing of the tympanic membrane between subjects who had single layer tympanoplasty and double layer tympanoplasty. Conclusion Tympanoplasty by double graft (temporalis fascia and tragal cartilage/perichondrium) achieved a considerable improvement in healing of the tympanic membrane ™ with lower risk for residual perforation or graft rejection.

Estrogen dampens central cannabinoid receptor 1-mediated neuroexcitation and pressor response in conscious female rats.

Activation of the rostral ventrolateral medulla (RVLM) cannabinoid receptor-1 (CB1R) causes neuronal nitric oxide synthase (nNOS)-dependent increases in sympathetic activity, blood pressure (BP) and heart rate (HR) in male rats. However, it remains unknown if the CB1R-mediated neurochemical and cardiovascular responses are influenced by the ovarian sex hormones, particularly estrogen (E2). Therefore, we studied the effects of intra-RVLM CB1R activation (WIN 55,212-2) on BP and HR in conscious female rats under the following hormonal states: (1) highest E2 level (proestrus sham-operated, SO); (2) E2-deprivation (ovariectomized, OVX); (3) OVX with E2 replacement (OVXE2). Intra-RVLM WIN55,212-2 elicited dose (100-400 pmol) dependent pressor and tachycardic responses, in OVX rats, which replicated the reported responses in male rats. However, in SO and OVXE2 rats, the CB1R-mediated pressor response was attenuated and the tachycardic response reverted to bradycardic response. The neurochemical findings suggested a key role for the upregulated RVLM sympathoexcitatory molecules phosphorated protein kinase B, phosphorated nNOS and reactive oxygen species in the exaggerated CB1R-mediated BP and HR responses in OVX rats, and an E2-dependent dampening of these responses. The intra-RVLM WIN55212-2-evoked cardiovascular and neurochemical responses were CB1R-mediated because they were attenuated by prior CB1R blockade (AM251). Our findings suggest that attenuation of RVLM neuroexcitation and oxidative stress underlies the protection conferred by E2, in female rats, against the CB1R-mediated adverse cardiovascular effects.

Predictive Value of Glycemia and Free Fatty Acid Levels upon Admission of Children with Scorpionism in Egypt.

Scorpion envenomation is a life-threatening emergency and causes serious health problems in tropical and subtropical regions. The aim of this study was to correlate the serum levels of biochemical parameters at admission in children with scorpion envenomation with subsequent morbidity and mortality. It was a prospective, observational, and descriptive study conducted for scorpion-envenomed children who presented to emergency and intensive care units between April 2019 and September 2019. Demographic, clinical, and laboratory findings of patients were recorded and tabulated. Routine investigations were done for all patients in addition to blood levels of lactate, free fatty acids (FFA), and insulin. All patients were compared according to outcome as survivors and nonsurvivors and according to glucose level as normoglycemic and hyperglycemic groups. There were 62 scorpion sting cases; their mean age was 8.6 ± 3.2 years. Patients aged more than 6 years (74.2%), and males (66.1%) were more affected than others. As regards severity, 25.8% were suffering organ dysfunction, 40.3% suffered systemic manifestations without organ dysfunction, and (33.9%) with only local manifestations. Serum glucose and FFA were significantly higher in nonsurvivors compared with survivors. Shock, convulsion, coma, heart failure, and pulmonary edema were significantly more common in hyperglycemic than normoglycemic group. Hyperglycemia, and raised FFA were associated with severe scorpion envenomation. Raised FFA was well correlated with presence of heart failure, leucocytosis, and hyperglycemia. Adding serum glucose and FFA to monitoring parameters of scorpionism severity can help the prediction of high-risk patients.

Hypothalamic kinin B1 receptor mediates orexin system hyperactivity in neurogenic hypertension.

Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.

Tetrahydrobiopterin paradoxically mediates cardiac oxidative stress and mitigates ethanol-evoked cardiac dysfunction in conscious female rats.

Oxidation of tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase (NOS), by reactive oxidative species (ROS), leads to NOS uncoupling and superoxide production instead of NO. Further, oxidative stress plays a major role in ethanol-evoked cardiac dysfunction in proestrus female rats, and acute ethanol administration reduces brain BH4 level. Therefore, we discerned the unknown role of BH4 in ethanol-evoked cardiac dysfunction by pharmacologically increasing BH4 levels or inhibiting its effect in proestrus female rats. Acute ethanol (1.5 g/kg, i.v, 30 min) caused myocardial dysfunction (lowered dP/dtmax and LVDP) and hypotension, along with increases in myocardial: (i) levels of NO, ROS and malondialdehyde (MDA), (ii) activities of catalase, ALDH2 and NADPH oxidase (Nox), and (iii) phosphorylation of eNOS, nNOS. Further, ethanol suppressed myocardial arginase and superoxide dismutase (SOD) activities and enhanced eNOS uncoupling. While ethanol had no effect on cardiac BH4 levels, BH4 (19 mg/kg, i.v) supplementation paradoxically caused cardiac oxidative stress, but mitigated the cardiac dysfunction/hypotension and most of the adverse molecular responses caused by ethanol. Equally important, the BH4 inhibitor DAHP (1 g/kg, i.p) exacerbated the adverse molecular and cardiovascular effects caused by ethanol. Our pharmacological studies support a protective role for the NOS co-factor BH4 against ethanol-evoked cardiac dysfunction and hypotension in female rats.

Probiotic capability of novel lactic acid bacteria isolated from worker honey bees gut microbiota.

The study aimed to evaluate the probiotic and safety properties of lactic acid bacterial (LAB) strains isolated from the gut microbiota of honey bee Apis mellifera L., since this source remains a promising reservoir of microbial diversity. A total of five bacterial isolates were molecularly identified using 16S rRNA gene sequencing as Enterococcus faecalis-HBE1, Lactobacillus brevis-HBE2, Enterococcus faecalis-HBE3, Enterococcus faecalis-HBE4 and Lactobacillus casei-HBE5. Gut tolerance conditions (low pH and bile salt) were evaluated. Exopolysaccharides (EPS) production, hemolytic, antioxidant activity, resistance toward antibiotics and technological characteristics (starter activity, pH and proteolysis) were examined. The five isolates showed a high survival rate (>95%), under gastrointestinal tract conditions indicating excellent potential for application as probiotics. The isolates showed no hemolytic activities and good acidification rates in the range of pH 4.6-4.98 after incubation at 37°C for 24h. The isolates exhibited promising proteolytic activity as well as DPPH radical scavenging activity in the range of 16.52-59.39%. All the tested isolates had the capability to produce exopolysaccharides except Lactobacillus casei-HBE5. These results put forward that lactic acid bacterial strain isolated from honey bee workers can be considered as promising candidates for future applications as starter cultures and could constitute new potential probiotics for the production of functional dietary products promoting health benefits.

Role of pERK1/2-NFκB signaling in the neuroprotective effect of thalidomide against cerebral ischemia reperfusion injury in rats.

In the present investigation, we tested the hypothesis that suppression of the phospho-extracellular signal regulated kinase (pERK1/2)-nuclear factor kappa (NFκ)-B signaling, subsequent to tumor necrosis factor-α (TNF-α) inhibition, underlies thalidomide (TLM) mediated neuroprotection. Male Wistar rats (250-280 g) were divided into five groups: (1) sham; (2) negative control receiving TLM (5µg/1µl/site) and 3 groups of ischemia-reperfusion (IR) injury rats pretreated with: (3) vehicle (DMSO 100%); (4) TLM (5µg/1µl/site) or (5) PD98059 (0.16µg/1µl/site). IR rats were subjected to occlusion of both common carotid arteries for 45 min followed by reperfusion for 24 h. Drugs and/or vehicles were administered by unilateral intrahippocampal injection after removal of the carotid occlusion and at the beginning of the reperfusion period. IR rats exhibited significant infarct size, histopathological damage, memory impairment, motor incoordination and hyperactivity. Unilateral intra-hippocampal TLM ameliorated these behavioral deficits along with the following ex vivo hippocampal effects: (i) abrogation of the IR-evoked elevations in hippocampal TNF-α, pERK1/2, NFκB, BDNF, iNOS contents and (ii) partial restoration of the reduced anti-inflammatory cytokine IL-10 and p-nNOS S852. These neurochemical effects, which were replicated by the pERK1/2 inhibitor PD98059, likely underlie the reductions in c-Fos and caspase-3 levels as well as the anti-apoptotic effect of TLM in the IR model. These results suggest a crucial anti-inflammatory role for pERK1/2 inhibition in the salutary neuronal and behavioral effects of TLM in a model of brain IR injury.

Alcohol suppresses cardiovascular diurnal variations in male normotensive rats: Role of reduced PER2 expression and CYP2E1 hyperactivity in the heart.

BACKGROUND AND AIMS: The molecular mechanism of the adverse effects of ethanol on diurnal cardiovascular regulation remains unknown. In separate studies, the cardiac circadian rhythm protein period-2 (PER2) confers cardioprotection and, in other organs, PER2 interaction with the ethanol-metabolizing enzyme CYP2E1 underlies, via heme oxygenase-1 (HO-1) upregulation, tissue injury/dysfunction. Here, we hypothesized that suppressed PER2 expression and elevated CYP2E1/HO-1 levels in the heart underlie the disrupted diurnal cardiovascular rhythm/function in alcohol-fed normotensive rats. METHODS: In ethanol-fed (5%, w/v; 8 weeks) or isocaloric liquid diet-fed male rats, diurnal changes in blood pressure (BP), heart rate (HR), HR vagal variability index, root mean square of successive beat-to-beat differences in beat-interval duration (rMSSD), and cardiac function were measured by radiotelemetry and echocardiography followed by ex vivo molecular studies. RESULTS: Radiotelemetry findings showed ethanol-evoked reductions in BP (during the dark cycle), rMSSD (during both cycles), and in diurnal differences in BP and rMSSD. Echocardiography findings revealed significant (p < 0.05) reductions in ejection fraction and fractional shortening (weeks 4-6) in the absence of cardiac remodeling (collagen content). Hearts of ethanol-fed rats exhibited higher (p < 0.05) CYP2E1 activity (50%) and HO-1 expression (63%), along with reduction (p < 0.05) in PER2 levels (29%), compared with the hearts of isocaloric diet-fed control rats. CONCLUSIONS: Our novel findings implicate upregulations of CYP2E1/HO-1 and downregulation of the circadian rhythm cardioprotective protein PER2, in the heart, in the chronic deleterious diurnal cardiovascular effects of alcohol in male rats.

Morphological and Interaction Characteristics of Surface-Active Ionic Liquids and Palmitic Acid in Mixed Monolayers.

A series of water soluble, surface-active ionic liquids (SAILs), namely, 1-alkyl-3-methyl imidazolium chlorides ([Cn -mim]Cl) and their mixtures with palmitic acid (PA) are investigated in Langmuir monolayers and Langmuir-Blodgett films. It is inferred from the surface pressure-area isotherms that C16 -mim-IL mixes non-ideally with PA and stabilizes the binary mixed films. In addition, the residence of mim-IL at the water surface is enhanced as a function of the increasing alkyl side chain length. Generally, the compressional moduli values decrease upon increasing the content of the mim-ILs over a wide range of compositions. Furthermore, film relaxation measurements indicate that the IL component is selectively excluded from the mixed films upon achieving a certain target pressure. Brewster angle microscope images demonstrate minimal changes on the PA domains in the presence of either C4 - and C8 -mim-ILs, whereas presence of the hexadecyl counterpart results in the formation of condensed sheets. Atomic force microscopy imaging of deposited films show the formation of propeller-like aggregates when C8 - or C16 -mim-IL is present in the mixed films.

Estrogen-dependent hypersensitivity to diabetes-evoked cardiac autonomic dysregulation: Role of hypothalamic neuroinflammation.

AIMS: To investigate if autonomic dysregulation is exacerbated in female rats, subjected to diabetes mellitus (DM), via a paradoxical estrogen (E2)-evoked provocation of neuroinflammation/injury of the hypothalamic paraventricular nucleus (PVN). MAIN METHODS: We measured cardiac autonomic function and conducted subsequent PVN neurochemical studies, in DM rats, and their respective controls, divided as follows: male, sham operated (SO), ovariectomized (OVX), and OVX with E2 supplementation (OVX/E2). KEY FINDINGS: Autonomic dysregulation, expressed as sympathetic dominance (higher low frequency, LF, band), only occurred in DM E2-replete (SO and OVX/E2) rats, and was associated with higher neuronal activity (c-Fos) and higher levels of TNFα and phosphorylated death associated protein kinase-3 (p-DAPK3) in the PVN. These proinflammatory molecules likely contributed to the heightened PVN oxidative stress, injury and apoptosis. The PVN of these E2-replete DM rats also exhibited upregulations of estrogen receptors, ERα and ERß, and proinflammatory adenosine A1 and A2a receptors. SIGNIFICANCE: The E2-dependent autonomic dysregulation likely predisposes DM female rats and women to hypersensitivity to cardiac dysfunction. Further, upregulations of proinflammatory mediators including adenosine A1 and A2 receptors, TNFα and DAPK3, conceivably explain the paradoxical hypersensitivity of DM females to PVN inflammation/injury and the subsequent autonomic dysregulation in the presence of E2.

Synthesis of novel naphthalene-heterocycle hybrids with potent antitumor, anti-inflammatory and antituberculosis activities.

Multitarget-directed drugs (hybrid drugs) constitute an efficient avenue for the treatment of multifactorial diseases. In this work, novel naphthalene hybrids with different heterocyclic scaffolds such as nicotinonitrile, pyran, pyranopyrazole, pyrazole, pyrazolopyridine, and azepine were efficiently synthesized via tandem reactions of 3-formyl-4H-benzo[h]chromen-4-one 1 with different nucleophilic reagents. Analysis of these hybrids using PASS online software indicated different predicted biological activities such as anticancer, antimicrobial, antiviral, antiprotozoal, anti-inflammatory, etc. By focusing on antitumor, anti-inflammatory, and antituberculosis activities, many compounds revealed remarkable activities. While 3c, 3e, and 3h were more potent than doxorubicin in the case of HepG-2 cell lines, 3a-e, 3i, 6, 8, 10, 11, and 12b were more potent in the case of MCF-7. Moreover, compounds 3c, 3h, 8, 10, 3d, and 12b manifested superior activity and COX-2 selectivity to the reference anti-inflammatory Celecoxib. Regarding antituberculosis activity, 3c, 3d, and 3i were found to be the most promising with MIC less than 1 µg mL-1. The molecular docking studies showed strong polar and hydrophobic interactions with the novel naphthalene-heterocycle hybrids that were compatible with experimental evaluations to a great extent.

Restoration of Adiponectin-Connexin43 Signaling Mitigates Myocardial Inflammation and Dysfunction in Diabetic Female Rats.

ur preclinical findings replicated women's hypersensitivity to type-2 diabetes mellitus (T2DM)-evoked cardiac dysfunction along with demonstrating estrogen (E2)-dependent disruption of the cardiac adiponectin (APN)-connexin43 (Cx43) signaling. Whether the latter molecular anomaly underlies this women's cardiovascular health problem remains unknown. We hypothesized that restoration of the disrupted APN-Cx43 signaling alleviates this sex/E2-dependent cardiac dysfunction in diabetic female rats. To test this hypothesis, we administered the adiponectin receptor 1 (AdipoR1) agonist AdipoRon (30 mg/kg/d for 10 days) to female sham operated (SO) and ovariectomized (OVX) rats, which exhibited and lacked the T2DM left ventricular (LV) dysfunction, respectively, when fed high-fat diet and received low dose streptozotocin regimen; nondiabetic control SO and OVX rats received control diet and vehicle for streptozotocin. In T2DM SO rats, LV dysfunction, AdipoRon mitigated: (1) LV hypertrophy, (2) reductions in fractional shortening, LV developed pressure, dP/dtmax, dP/dtmin, and Tau. In LV tissues of the same rats, AdipoRon reversed reduction in Cx43 and elevations in TNFα, heme-oxygenase 1 (HO-1), and circulating cardiovascular risk factor asymmetric dimethylarginine. The findings also revealed ovarian hormones independent effects of AdipoRon, which included dampening of the pro-oxidant enzyme HO-1. These novel findings yield new insight into a causal role for compromised APN-Cx43 signaling in the E2-dependent hypersensitivity to T2DM-evoked cardiac inflammation and dysfunction. Equally important, the findings identify restoration of Cx43 signaling as a viable therapeutic modality for alleviating this women's cardiovascular health-related problem.

Aldehyde Dehydrogenase Inhibition Ameliorates Cardiac Dysfunction and Exacerbates Hypotension Caused by Alcohol in Female Rats.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) protects against alcohol-evoked cardiac dysfunction in male rodents, but its role in the estrogen (E2 )-dependent hypersensitivity of female rats to alcohol-evoked myocardial oxidative stress and dysfunction is not known. METHODS: We addressed this question by studying the effect of cyanamide (ALDH2 inhibitor) on cardiac function, blood pressure, alcohol-metabolizing enzyme (alcohol dehydrogenase, cytochrome P450 2E1, catalase, and ALDH2) activities, and cardiac redox status (reactive oxygen species, ROS; malondialdehyde, MDA) in the absence or presence of ethanol (EtOH) in female sham-operated (SO) and ovariectomized (OVX) rats. RESULTS: Cyanamide attenuated the EtOH-evoked myocardial dysfunction (reduced dP/dtmax and LVDP) in SO rats. EtOH, cyanamide, or their combination did not alter dP/dtmax or LVDP in OVX rats. Cyanamide induced cardiac oxidative stress and abrogated the subsequent alcohol-evoked increases in ROS and MDA levels in SO rats. Neither EtOH nor cyanamide influenced ROS or MDA levels in OVX rats. Importantly, cyanamide exaggerated EtOH-evoked hypotension in SO and uncovered this hypotensive response in OVX rats, which implicates ALDH2 in the vasodilating effect of EtOH. CONCLUSIONS: Contrary to our hypothesis, cyanamide attenuated the E2 -dependent cardiac dysfunction caused by alcohol, likely by preconditioning the heart to oxidative stress, while exacerbating the vasodilating effect of alcohol. The latter might predispose to syncope when cyanamide and alcohol are combined in females.

Role of Alcohol Oxidative Metabolism in Its Cardiovascular and Autonomic Effects.

Several review articles have been published on the neurobehavioral actions of acetaldehyde and other ethanol metabolites as well as in major alcohol-related disorders such as cancer and liver and lung disease. However, very few reviews dealt with the role of alcohol metabolism in the adverse cardiac and autonomic effects of alcohol and their potential underlying mechanisms, particularly in vulnerable populations. In this chapter, following a brief overview of the dose-related favorable and adverse cardiovascular effects of alcohol, we discuss the role of ethanol metabolism in its adverse effects in the brainstem and heart. Notably, current knowledge dismisses a major role for acetaldehyde in the adverse autonomic and cardiac effects of alcohol because of its low tissue level in vivo. Contrary to these findings in men and male rodents, women and hypertensive individuals are more sensitive to the adverse cardiac effects of similar amounts of alcohol. To understand this discrepancy, we discuss the autonomic and cardiac effects of alcohol and its metabolite acetaldehyde in a model of hypertension, the spontaneously hypertensive rat (SHR) and female rats. We present evidence that enhanced catalase activity, which contributes to cardioprotection in hypertension (compensatory) and in the presence of estrogen (inherent), becomes detrimental due to catalase catalysis of alcohol metabolism to acetaldehyde. Noteworthy, studies in SHRs and in estrogen deprived or replete normotensive rats implicate acetaldehyde in triggering oxidative stress in autonomic nuclei and the heart via (i) the Akt/extracellular signal-regulated kinases (ERK)/nitric oxide synthase (NOS) cascade and (ii) estrogen receptor-alpha (ERα) mediation of the higher catalase activity, which generates higher ethanol-derived acetaldehyde in female heart. The latter is supported by the ability of ERα blockade or catalase inhibition to attenuate alcohol-evoked myocardial oxidative stress and dysfunction. More mechanistic studies are needed to further understand the mechanisms of this public health problem.

Estrogen-Dependent Disruption of Adiponectin-Connexin43 Signaling Underlies Exacerbated Myocardial Dysfunction in Diabetic Female Rats.

The reasons for the higher severity of type 2 diabetes (T2DM)-associated cardiomyopathy in women, despite their inherent estrogen (E2)-dependent cardioprotection, remain unknown. We hypothesized that the reliance of the healthy females' hearts on augmented adiponectin (APN)-connexin 43 (Cx43) signaling becomes paradoxically detrimental when disrupted by T2DM in an E2-dependent manner. We tested this hypothesis in high-fat, low- dose streptozotocin diabetic rats and their controls with the following designations: 1) sham-operated (SO), 2) ovariectomized (OVX), 3) ovariectomized with E2 supplementation (OVX + E2), and 4) male. E2-replete (SO or OVX + E2) diabetic rats exhibited higher mortality and greater increases in left ventricular (LV) mass and reduced LV developed pressure, LV contractility, and fractional shortening but preserved ejection fraction. Further, compared with respective nondiabetic counterparts, the hearts of these E2-replete diabetic rats exhibited greater upregulation of cardiac estrogen receptor α and reductions in Cx43 expression and in the phosphorylation levels of the survival molecules extracellular regulating kinases 1/2 and phosphorylated AKT (pAKT). Whereas serum APN was reduced, independent of sex and ovarian hormone status in all DM rats, cardiac APN was most drastically reduced in DM SO rats. The present translational findings are the first to implicate ovarian hormones/E2 in the exacerbated myocardial dysfunction in female diabetic subjects and to suggest a pivotal role for malfunctioning cardiac APN-Cx43 signaling in this sex/E2-specific clinical problem.