The expression of KLF11 (TIEG2), a monoamine oxidase B transcriptional activator in the prefrontal cortex of human alcohol dependence.

BACKGROUND: The biochemical pathways underlying alcohol abuse and dependence are not well understood, although brain cell loss and neurotoxicity have been reported in subjects with alcohol dependence. Monoamine oxidase B (MAO B; an enzyme that catabolizes neurotransmitters such as dopamine) is consistently increased in this psychiatric illness. MAO B has been implicated in the pathogenesis of alcohol dependence and alcohol-induced brain neurotoxicity. Recently, the cell growth inhibitor protein, Kruppel-like factor 11 (KLF11), has been reported to be an MAO transcriptional activator. KLF11 is also known as TIEG2 (transforming growth factor-beta-inducible early gene 2) and mediates apoptotic cell death. This study investigates the protein expression of KLF11 and its relationship with MAO B using human postmortem prefrontal cortex from subjects with alcohol dependence. METHODS: Twelve subjects with alcohol dependence and the respective psychiatrically normal control subjects were investigated. Expression of KLF11 and MAO B proteins in the prefrontal cortex was measured by Western blot analysis. Correlation studies involving KLF11 and MAO B protein expression were performed. Localization of KLF11 in the human prefrontal cortex was also determined by immunohistochemistry. RESULTS: Levels of KLF11 protein were significantly increased by 44% (p < 0.03) in the postmortem prefrontal cortex of subjects with alcohol dependence as compared to age- and gender-matched, psychiatrically normal control subjects. Furthermore, KLF11 levels were significantly and positively correlated with both the increased MAO B protein levels and blood alcohol content in alcohol-dependent subjects. In addition, KLF11 protein expression was visualized in both neuronal and glial cells. CONCLUSIONS: This novel study shows the important role of KLF11, an MAO transcriptional activator, in human alcohol dependence. It further supports that the KLF11-MAO B cell death cascade may contribute to chronic alcohol-induced brain damage. This argues a case for KLF11-MAO B inhibition as a novel therapeutic strategy that may impact this highly prevalent illness.

Diabetes-causing gene, kruppel-like factor 11, modulates the antinociceptive response of chronic ethanol intake.

BACKGROUND: Alcohol (EtOH [ethanol]) is an antinociceptive agent, working in part, by reducing sensitivity to painful stimuli. The transcription factor Kruppel-like factor 11 (KLF11), a human diabetes-causing gene that also regulates the neurotransmitter metabolic enzymes monoamine oxidase (MAO), has recently been identified as an EtOH-inducible gene. However, its role in antinociception remains unknown. Consequently, we investigated the function of KLF11 in chronic EtOH-induced antinociception using a genetically engineered knockout mouse model. METHODS: Wild-type (Klf11(+/+) ) and KLF11 knockout (Klf11(-/-) ) mice were fed a liquid diet containing EtOH for 28 days with increasing amounts of EtOH from 0% up to a final concentration of 6.4%, representing a final diet containing 36% of calories primarily from EtOH. Control mice from both genotypes were fed liquid diet without EtOH for 28 days. The EtOH-induced antinociceptive effect was determined using the tail-flick test before and after EtOH exposure (on day 29). In addition, the enzyme activity and mRNA levels of MAO A and MAO B were measured by real-time RT-PCR and enzyme assays, respectively. RESULTS: EtOH produced an antinociceptive response to thermal pain in Klf11(+/+) mice, as expected. In contrast, deletion of KLF11 in the Klf11(-/-) mice abolished the EtOH-induced antinociceptive effect. The mRNA and protein levels of KLF11 were significantly increased in the brain prefrontal cortex of Klf11(+/+) mice exposed to EtOH compared with control Klf11(+/+) mice. Furthermore, MAO enzyme activities were affected differently in Klf11 wild-type versus Klf11 knockout mice exposed to chronic EtOH. Chronic EtOH intake significantly increased MAO B activity in Klf11(+/+) mice. CONCLUSIONS: The data show KLF11 modulation of EtOH-induced antinociception. The KLF11-targeted MAO B enzyme may contribute more significantly to EtOH-induced antinociception. Thus, this study revealed a new role for the KLF11 gene in the mechanisms underlying the antinociceptive effects of chronic EtOH exposure.

Differences in clinical presentation and outcomes in pregnancy-associated Takotsubo Syndrome- A scoping review of the literature: Outcomes in pregnancy-associated Takotsubo.

BACKGROUND: Takotsubo syndrome (TS) during pregnancy and postpartum is rare but may lead to significant maternal and fetal morbidity. We compared clinical characteristics and prognosis according to [a] timing of presentation (pregnancy vs post-partum) and [b] modes of delivery (cesarean section vs vaginal delivery). METHODS: Systematic review of articles published in PubMed, Scopus, Embase, and Medline databases from inception to July 30, 2023. Patient demographics, obstetric, electrocardiographic, laboratory, echocardiographic characteristics, and prognosis were summarized descriptively. RESULTS: An initial database search identified 2162 articles, of which 81 studies were included in this review. TS during pregnancy can have emotional, obstetric, and metabolic triggers and has a higher proportion of adverse fetal outcomes when compared with women who developed TS postpartum. Women with TS after cesarean section had an earlier onset and higher proportion of anesthesia use when compared with those who developed TS after vaginal delivery. There were no differences regarding the degree of systolic dysfunction or the need for advanced therapies, including ventilator support, intra-aortic balloon pump, and extracorporeal membrane oxygenation among groups. CONCLUSIONS: TS is associated with various triggers and adverse fetal outcomes when it develops during pregnancy than in the postpartum period. TS occurs more rapidly and with a more aggressive course after cesarean section than after vaginal delivery.

Convergent effects of acute stress and glucocorticoid exposure upon MAO-A in humans.

Monoamine oxidase-A (MAO-A), a key brain enzyme which metabolizes monoamines, is implicated in the pathophysiology of stress-related illnesses, including major depressive disorder, addiction, and violent behavior. Chronic stressors and glucocorticoid-administration typically associate with elevated MAO-A levels/activity. However, the relationship of shorter stress or glucocorticoid exposures and MAO-A levels/activity is not well established. Our objectives are to assess effects of acute stress upon MAO-A V(T,) an index of MAO-A density, in human brain and acute glucocorticoid exposure upon MAO-A levels in human neuronal and glial cell lines. Twelve healthy, non-smoking participants aged 18-50 underwent [(11)C]harmine positron emission tomography to measure brain MAO-A V(T) on two different days: One under acute psychosocial stress (via Trier Social Stress and Montreal Imaging Stress Tasks) and one under a non-stress condition. MAO-A density (by Western blot) and activity (by [(14)C]-5-HT metabolism and liquid scintillation spectroscopy) were measured in human neuronal and glial cell lines after 4 h exposure to dexamethasone. We observed a significant reduction in whole-brain MAO-A binding as reflected by reductions in 10 of 11 brain regions. Acute dexamethasone exposure in neuronal and glial cells significantly decreased MAO-A activity and protein levels. We observed a highly consistent relationship between acute stressors and glucocorticoid administration and decreased MAO-A binding, activity and protein levels. Since MAO-A metabolizes monoamines, this phenomenon may explain why acute stressors benefit healthy animals even though chronic stress is associated with illness.

A case report of an unusual left atrial mass.

BACKGROUND: Cardiac foreign bodies (FBs) are rare findings that may present as cardiac masses initially. Here, we present an exceptional and rare case of a hypodermic needle FB that transmigrated to the left atrium and presented as a left atrial mass. CASE SUMMARY: A 28-year-old woman with multiple psychiatric disorders including intentional FB ingestion and self-inflicting injuries presented to the emergency room with abdominal pain, nausea, vomiting, diarrhoea, and chest pain that radiated to the left arm and face for 2 weeks. An echocardiogram was performed revealing a left atrial mass concerning for myxoma. During the surgical removal of the mass, a hypodermic needle was found attached to the roof of the left atrium surrounded by thrombotic and fibrotic tissue, which was confirmed by pathology. DISCUSSION: Cardiac FBs are caused generally by penetrating wounds from direct trauma. Fewer cases have been reported regarding cardiac FB caused by ingestion from migration of the object to the heart. Signs and symptoms for cardiac FB may mimic those of cardiac masses. Cardiac FBs often require surgical intervention to avoid complications.

Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury.

Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial. In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague-Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol. Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge. These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities.

Evidence revealing deregulation of the KLF11-MAO A pathway in association with chronic stress and depressive disorders.

The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (p<0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (p<0.02) in the frontal cortex of KLF11 wild-type mice (Klf11(+/+)) vs Klf11(-/-) when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11(+/+) mice, suggesting that Klf11(+/+) mice are more severely affected by the stress model compared with Klf11(-/-) mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.