ABSTRACT
Background: Cardiogenic shock (CS) complicating myocardial infarction is associated with poor outcomes. Data among Asian populations are scarce. We aimed to investigate the long-term outcomes, prognostic factors, and predictors of CS among Asian ST elevation myocardial infarction (STEMI) patients. Methods: This was a retrospective cohort study of consecutive patients undergoing primary percutaneous coronary intervention (PPCI) for STEMI within our regional STEMI network between 2015 and 2019. The long-term outcomes of those with and without CS were compared. Clinical predictors of outcomes and development of CS were investigated. Results: A total of 1791 patients who underwent PPCI were included. Patients completed at least 2 years' follow-up with a median follow-up period of 2.6 years (IQR 1.0, 3,9). Overall, 208/1791 (11.6 %) STEMI patients developed CS. These patients were older (61.1 ± 12.5 vs 57.8 ± 12.2, P < 0.001) and mostly men (87.0 %). All-cause mortality (59.9 % vs 4.7 % P < 0.001), cardiac mortality (43.8 % vs 2.2 %, P < 0.001) and major adverse cardiovascular events (MACE) was significantly higher in the CS group (59.1 % vs 14.0 %, P < 0.001). Independent predictors of survival were higher index LVEF (adjusted hazards ratio [aHR] 0.967, 95 %CI 0.951-0.984, p < 0.001) and higher arterial pH at onset of shock (aHR 0.750, 0.626-0.897, p = 0.002). Increased serum lactate concentration independently predicts poor prognosis (aHR 1.084, 95 % CI 1.046-1.124, p < 0.001). Conclusion: In Asian STEMI patients who underwent PPCI, CS was associated with poor outcomes. Higher LVEF on index admission was associated with better outcomes; while lactic acidosis independently predicted mortality.
ABSTRACT
Genetic toxicology, strategically located at the intersection of genetics and toxicology, aims to demystify the complex interplay between exogenous agents and our genetic blueprint. Telomeres, the protective termini of chromosomes, play instrumental roles in cellular longevity and genetic stability. Traditionally karyotyping and fluorescence in situ hybridisation (FISH), have been indispensable tools for chromosomal analysis following exposure to genotoxic agents. However, their scope in discerning nuanced molecular dynamics is limited. Peptide Nucleic Acids (PNAs) are synthetic entities that embody characteristics of both proteins and nucleic acids and have emerged as potential game-changers. This perspective report comprehensively examines the vast potential of PNAs in genetic toxicology, with a specific emphasis on telomere research. PNAs' superior resolution and precision make them a favourable choice for genetic toxicological assessments. The integration of PNAs in contemporary analytical workflows heralds a promising evolution in genetic toxicology, potentially revolutionizing diagnostics, prognostics, and therapeutic avenues. In this timely review, we attempted to assess the limitations of current PNA-FISH methodology and recommend refinements.
Subject(s)
In Situ Hybridization, Fluorescence , Peptide Nucleic Acids , Telomere , Telomere/drug effects , Telomere/genetics , Humans , In Situ Hybridization, Fluorescence/methods , Animals , Mutagens/toxicity , Karyotyping/methodsABSTRACT
Physiological processes that govern the normal functioning of mammalian cells are regulated by a myriad of signalling pathways. Mammalian mitogen-activated protein (MAP) kinases constitute one of the major signalling arms and have been broadly classified into four groups that include extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and ERK5. Each signalling cascade is governed by a wide array of external and cellular stimuli, which play a critical part in mammalian cells in the regulation of various key responses, such as mitogenic growth, differentiation, stress responses, as well as inflammation. This evolutionarily conserved MAP kinase signalling arm is also important for metabolic maintenance, which is tightly coordinated via complicated mechanisms that include the intricate interaction of scaffold proteins, recognition through cognate motifs, action of phosphatases, distinct subcellular localisation, and even post-translational modifications. Aberration in the signalling pathway itself or their regulation has been implicated in the disruption of metabolic homeostasis, which provides a pathophysiological foundation in the development of metabolic syndrome. Metabolic syndrome is an umbrella term that usually includes a group of closely associated metabolic diseases such as hyperglycaemia, hyperlipidaemia, and hypertension. These risk factors exacerbate the development of obesity, diabetes, atherosclerosis, cardiovascular diseases, and hepatic diseases, which have accounted for an increase in the worldwide morbidity and mortality rate. This review aims to summarise recent findings that have implicated MAP kinase signalling in the development of metabolic diseases, highlighting the potential therapeutic targets of this pathway to be investigated further for the attenuation of these diseases.
ABSTRACT
AIM: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined. METHODS: This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan-Meier curve was constructed for long-term all-cause mortality. Cox regression analysis was used to investigate independent predictors of long-term all-cause mortality. RESULTS: In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow-up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all-cause mortality (6.8% vs. 3.6%, p < .001) at 30 days, with unfavourable mortality rates sustained in the long-term (18.3% vs. 14.5%, p = .001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long-term all-cause mortality (hazard ratio 1.330, 95% confidence interval 1.106-1.598, p = .002). CONCLUSION: MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long-term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI.
Subject(s)
Myocardial Infarction , Propensity Score , Humans , Male , Female , Myocardial Infarction/mortality , Myocardial Infarction/complications , Myocardial Infarction/epidemiology , Middle Aged , Prognosis , Aged , Singapore/epidemiology , Fatty Liver/complications , Fatty Liver/mortality , Risk Factors , Retrospective StudiesABSTRACT
Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis. Using advanced mass spectrometry, we profiled the proteome and phosphoproteome of heart tissues obtained from mice that were maintained on daily 12- or 16 hr fasting, every-other-day fasting, or ad libitum control feeding regimens for 6 months. We also performed RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. Our analyses revealed that IF significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Furthermore, we found that the impact of IF on different metabolic processes varied depending on the length of the fasting regimen. Short IF regimens showed a higher correlation of pathway alteration, while longer IF regimens had an inverse correlation of metabolic processes such as fatty acid oxidation and immune processes. Additionally, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. Our systematic multi-omics study provides a molecular framework for understanding how IF impacts the heart's function and its vulnerability to injury and disease.
Subject(s)
Intermittent Fasting , Multiomics , Humans , Mice , Animals , Proteome , Fasting/physiology , Energy MetabolismABSTRACT
In the laboratory, visual search is often studied using uniform backgrounds. This contrasts with search in daily life, where potential search items appear against more complex backgrounds. In the present study, we examined the effects of background complexity on a parallel visual search under conditions where objects are easily segregated from the background. Target-distractor similarity was sufficiently low such that search could unfold in parallel, as indexed by reaction times that increase logarithmically with set size. The results indicate that when backgrounds are relatively simple (sandy beach with water elements), search efficiency is comparable to search using a solid background. When backgrounds are more complex (child bedroom or checkerboard), logarithmic search slopes increase compared to search on solid backgrounds, especially at higher levels of target-distractor similarity. The results are discussed in terms of different theories of visual search. It is proposed that the complex visual information occurring in between distractors slows down individual distractor rejection times by weakening the strength of interitem interactions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Subject(s)
Attention , Visual Perception , Humans , Reaction TimeABSTRACT
Breast cancer is the most common cause of malignancy and the second most common cause of death due to cancer in women. This heterogeneous disease is currently broadly classified as estrogen receptor (ER), progesterone receptor (PR) positive luminal tumors, human epidermal growth factor receptor 2 (HER2) amplified tumors and triple-negative breast cancers (TNBC). Phytochemicals are proven to be promising anti-cancer chemotherapeutics agents with minimal cytotoxic effects on normal cells. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is a phytochemical derived from the roots of Plumbago zeylanica and it is known to possess anti-cancer properties similar to other compounds of naphthoquinones. In about 90% of cancer cells, the telomerase enzyme activity is revived to add telomeric repeats to evade apoptosis. In this study, a combinatorial approach of combining the anti-cancer compound plumbagin to induce genotoxicity and a potent telomerase inhibitor, MST-312 (synthetic derivative of tea catechins), was used to determine the combinational treatment-induced lethality in breast cancer cells such as MDA-MB-231 (TNBC) and MCF-7 (lumina) cells. MDA-MB-231 cells were responsive to combination treatment in both short-term (48 h) and long-term treatment (14 days) in a synergistic manner, whereas in MCF-7, the combination treatment was more effective in the long-term regimen. Furthermore, the cytotoxic effects of the plumbagin and MST-312 combination treatment were not recoverable after the short-term treatment. In conclusion, a combination treatment of MST-312 and plumbagin is proven to be more effective than a single plumbagin compound treatment in inducing DNA damage and telomere dysfunction leading to greater genome instability, cell cycle arrest and eventually cell death in cancer cells.
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Background: An increasing proportion of patients with acute myocardial infarction (AMI) are presenting without standard modifiable risk factors (SMuRFs) of hypertension, hypercholesterolemia, diabetes, and smoking, but with an unexpectedly increased mortality. This study examined the SMuRF-less patients presenting with AMI in a multiethnic Asian population. Methods: We recruited patients presenting with AMI from 2011 to 2021 and compared the prevalence, clinical characteristics, and outcomes of SMuRF-less and SMuRF patients. Multivariable analysis was used to compare the outcomes of 30-day cardiovascular mortality, all-cause mortality, readmission, cardiogenic shock, stroke, and heart failure. Kaplan-Meier curves were constructed for 30-day cardiovascular mortality, with stratification by ethnicity, gender and AMI type, and 10-year all-cause mortality. Results: Standard modifiable risk factor-less patients, who made up 8.6% of 8,680 patients, were significantly younger with fewer comorbidities that include stroke and chronic kidney disease, but higher rates of ventricular arrhythmias and inotropic or invasive ventilation requirement. Multivariable analysis showed higher rates of cardiovascular mortality (HR 1.48, 95% CI: 1.09-1.86, p = 0.048), cardiogenic shock (RR: 1.31, 95% CI: 1.09-1.52, p = 0.015), and stroke (RR: 2.51, 95% CI: 1.67-3.34, p = 0.030) among SMuRF-less patients. A 30-day cardiovascular mortality was raised in the SMuRF-less group, with similar trends in men, patients with ST-segment elevation myocardial infarction (STEMI), and the three Asian ethnicities. All-cause mortality remains increased in the SMuRF-less group for up to 5 years. Conclusion: There is a significant proportion of patients with AMI without standard risk factors in Asia, who have worse short-term mortality. This calls for greater focus on the management of this unexpectedly high-risk subgroup of patients.
ABSTRACT
Telomeres play a critical role in maintaining cellular fate through tight regulation of cell division and DNA damage or repair. Over the years, it is established that biological ageing is defined by a gradual derangement in functionality, productivity, and robustness of biological processes. The link between telomeres and ageing is highlighted when derangement in telomere biology often leads to premature ageing and concomitant accompaniment of numerous age-associated diseases. Unfortunately, given that ageing is a biologically complicated intricacy, measures to reduce morbidity and improve longevity are still largely in the infancy stage. Recently, it was discovered that dietary habits and interventions might play a role in promoting successful healthy ageing. The intricate relationship between dietary components and its potential to protect the integrity of telomeres may provide unprecedented health benefits and protection against age-related pathologies. However, more focused prospective and follow-up studies with and without interventions are needed to unequivocally link dietary interventions with telomere maintenance in humans. This review aims to summarise recent findings that investigate the roles of nutrition on telomere biology and provide enough evidence for further studies to consider the topic of nutrigenomics and its contributions toward healthy ageing and concomitant strategy against age-associated diseases.
Subject(s)
DNA Damage , Telomere , Diet , Humans , Prospective Studies , Telomere/geneticsABSTRACT
Intermittent fasting (IF) remains the most effective intervention to achieve robust anti-aging effects and attenuation of age-related diseases in various species. Epigenetic modifications mediate the biological effects of several environmental factors on gene expression; however, no information is available on the effects of IF on the epigenome. Here, we first found that IF for 3 months caused modulation of H3K9 trimethylation (H3K9me3) in the cerebellum, which in turn orchestrated a plethora of transcriptomic changes involved in robust metabolic switching processes commonly observed during IF. Second, a portion of both the epigenomic and transcriptomic modulations induced by IF was remarkably preserved for at least 3 months post-IF refeeding, indicating that memory of IF-induced epigenetic changes was maintained. Notably, though, we found that termination of IF resulted in a loss of H3K9me3 regulation of the transcriptome. Collectively, our study characterizes the novel effects of IF on the epigenetic-transcriptomic axis, which controls myriad metabolic processes. The comprehensive analyses undertaken in this study reveal a molecular framework for understanding how IF impacts the metabolo-epigenetic axis of the brain and will serve as a valuable resource for future research.
Subject(s)
Epigenomics , Transcriptome , Fasting , Gene Expression Profiling , BrainABSTRACT
BACKGROUND: The clinical significance of coronary artery ectasia (CAE) is not yet fully understood. We aimed to examine differences in clinical and procedural characteristics, clinical management, and outcomes in patients with CAE undergoing primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). METHODS: This was a retrospective analysis of consecutive patients presenting with STEMI with a culprit native coronary artery from July 2015 to June 2019. Patients were divided into CAE and Non-CAE groups as detected on coronary angiography during PPCI. Comparison between groups was made for baseline clinical and procedural characteristics, as well as complications, pharmacological treatment, and follow-up outcomes. RESULTS: 36/1780 (2.0%) patients were found to have CAE. Patients with CAE had a median age of 57.1 ± 11.7 years and were more likely to be male 33/36 (91.7%). Diabetes was less commonly seen in the CAE group (11.1% vs 31.4%, p = 0.010), and there were no differences in the proportion of patients with hypertension and hyperlipidemia. Patients with CAE had more involvement of right coronary artery (RCA) culprit vessel (63.9% vs. 38.4%, p = 0.026), less coronary stenting (25.0% vs 87.2%, p < 0.001) and post-PPCI TIMI 3 flow (69.4% vs 95.5%, P < 0.001), and were more likely to be discharged with oral anticoagulants (36.1% vs 7.6%, p < 0.001). At 3-year follow-up, all-cause mortality rates were higher in the non-CAE group (0.0% vs 11.5%, p < 0.028), suggesting that CAE was not associated with unfavorable long-term outcome. On multivariate analysis, CAE was not an independent predictor of MACE. CONCLUSION: Despite lower rates of post-PPCI TIMI 3 flow, CAE was not associated with unfavorable long-term outcome.
Subject(s)
Coronary Aneurysm , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Aged , Coronary Aneurysm/etiology , Coronary Angiography/adverse effects , Coronary Vessels/diagnostic imaging , Dilatation, Pathologic/complications , Female , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Retrospective Studies , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/therapy , Treatment OutcomeABSTRACT
The pandemic has led to adverse short-term outcomes for patients with ST-segment elevation myocardial infarction (STEMI). It is unknown if this translates to poorer long-term outcomes. In Singapore, the escalation of the outbreak response on February 7, 2020 demanded adaptation of STEMI care to stringent infection control measures. A total of 321 patients presenting with STEMI and undergoing primary percutaneous coronary intervention at a tertiary hospital were enrolled and followed up over 1-year. They were allocated into three groups based on admission date-(1) Before outbreak response (BOR): December 1, 2019-February 6, 2020, (2) During outbreak response (DOR): February 7-March 31, 2020, and (3) control group: November 1-December 31, 2018. The incidence of cardiac-related mortality, cardiac-related readmissions, and recurrent coronary events were examined. Although in-hospital outcomes were worse in BOR and DOR groups compared to the control group, there were no differences in the 1-year cardiac-related mortality (BOR 8.7%, DOR 7.1%, control 4.8%, p = 0.563), cardiac-related readmissions (BOR 15.1%, DOR 11.6%, control 12.0%, p = 0.693), and recurrent coronary events (BOR 3.2%, DOR 1.8%, control 1.2%, p = 0.596). There were higher rates of additional PCI during the index admission in DOR, compared to BOR and control groups (p = 0.027). While patients admitted for STEMI during the pandemic may have poorer in-hospital outcomes, their long-term outcomes remain comparable to the pre-pandemic era.
Subject(s)
COVID-19 , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Humans , Pandemics , Patient Readmission/statistics & numerical data , Recurrence , ST Elevation Myocardial Infarction/epidemiology , ST Elevation Myocardial Infarction/surgery , Singapore/epidemiology , Tertiary Care Centers , Treatment OutcomeABSTRACT
Visual working memory (VWM) content disrupts visual search performance when there is a singleton in the search array that is similar to the content in VWM, even when this singleton is task irrelevant. Typically, the memory-similar singleton captures attention, which results in slower search performance for memory-similar conditions compared to conditions where memory-similar content is absent. Recently, it has also been shown that VWM content may be affected when memory-similar stimuli are processed. Specifically, it appears that VWM representations bias toward memory-similar information that is processed but not memory-dissimilar information. Here, we test whether the bias caused by processing memory-similar information is an active interference process (growing with engagement with the memory-similar stimuli) or a passive interference process (indifferent to the engagement with memory-similar stimuli). To test this, observers were tasked with memorizing a single color followed by a search task. The search task was either easy or difficult, and the search items could either be memory-similar or memory-dissimilar. Critically, the target in the search task was defined by its shape, so the color of the search items was irrelevant to the search task. At the end of each trial, participants reported the color in memory using a continuous report color wheel. The results showed that VWM representations drifted towards the irrelevant color of the search items in the memory-similar conditions, and this effect was larger in the difficult search condition. The results provide evidence that VWM representations receive active interference from processing memory-similar stimuli.
Subject(s)
Memory, Short-Term , Visual Perception , Attention , Humans , Memory DisordersABSTRACT
A common assumption in attention theories is that attention prioritizes search items based on their similarity to the target. Here, we tested this assumption and found it wanting. Observers searched through displays containing candidates (distractors that cannot be confidently differentiated from the target by peripheral vision) and lures (distractors that can be). Candidates had high or low similarity to the target. Search displays were either candidate-homogeneous (all items of same similarity) or candidate-heterogeneous (equal numbers of each similarity). Response times to candidate-heterogeneous displays were equivalent to the average of high- and low-similarity displays, suggesting that attention was allocated randomly, rather than toward the high-similarity candidates first. Lures added a response time cost that was independent of the candidates, suggesting they were rejected prior to candidates being inspected. These results suggest a "reverse" prioritization process: Distributed attention discards least target-similar items first, while focused spatial attention is randomly directed to target-similar items. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Subject(s)
Pattern Recognition, Visual , Visual Perception , Humans , Reaction TimeABSTRACT
BACKGROUND: COVID-19 infection is the most serious global public health crisis of the century. With no approved treatments against it, investigational treatments are being used despite limited safety data. Besides being at higher risk of complications of COVID-19 infection, patients with underlying cardiovascular disease are more likely to develop cardiac-related side effects of treatment. We present a case of sinus arrest with junctional escape related to lopinavir-ritonavir. CASE SUMMARY: A 67-year-old man, with underlying stable ischaemic heart disease, acquired COVID-19 infection. He had a prolonged duration of fever and cough. He subsequently developed acute respiratory distress and required intensive care unit (ICU) care. Given his severe infection, he was started on lopinavir-ritonavir. Hydroxychloroquine was not used as he had a prolonged QTc interval. During observation in the ICU, the patient developed recurrent episodes of sinus arrest with junctional escape. Initial concerns were of myocarditis, but he had no ST-segment changes on ECG, with mild elevations of highly sensitive troponin I and a normal transthoracic echocardiogram. A multidisciplinary team discussion involving the intensivist, infectious disease physicians, and cardiologist; the decision was made to stop treatment with lopinavir-ritonavir. Within 48 h, the bradyarrhythmia resolved. The patient did not require transvenous and permanent pacemaker insertion. CONCLUSION: Current efficacy and safety evidence of lopinavir-ritonavir as a treatment in COVID-19 patients is limited. Although uncommonly reported, those with underlying cardiovascular disease are at increased risk of bradyarrhythmia-related adverse effects of lopinavir-ritonavir. When initiating investigational therapies, especially in patients with cardiovascular conditions, adequate counselling and close monitoring are required.
ABSTRACT
Feature Integration Theory (FIT) set out the groundwork for much of the work in visual cognition since its publication. One of the most important legacies of this theory has been the emphasis on feature-specific processing. Nowadays, visual features are thought of as a sort of currency of visual attention (e.g., features can be attended, processing of attended features is enhanced), and attended features are thought to guide attention towards likely targets in a scene. Here we propose an alternative theory - the Target Contrast Signal Theory - based on the idea that when we search for a specific target, it is not the target-specific features that guide our attention towards the target; rather, what determines behavior is the result of an active comparison between the target template in mind and every element present in the scene. This comparison occurs in parallel and is aimed at rejecting from consideration items that peripheral vision can confidently reject as being non-targets. The speed at which each item is evaluated is determined by the overall contrast between that item and the target template. We present computational simulations to demonstrate the workings of the theory as well as eye-movement data that support core predictions of the theory. The theory is discussed in the context of FIT and other important theories of visual search.
Subject(s)
Eye Movements/physiology , Goals , Models, Theoretical , Reaction Time/physiology , Visual Perception/physiology , Attention/physiology , Cognition , Female , Humans , Male , Young AdultABSTRACT
During production of the article, Figure 4 was incorrectly used twice in the initial article, so it appeared both as Figure 4 and Figure 5 in the article.
ABSTRACT
Scope: Intermittent fasting (IF) has been extensively reported to promote improved energy homeostasis and metabolic switching. While IF may be a plausible strategy to ameliorate the epidemiological burden of disease in many societies, our understanding of the underlying molecular mechanisms behind such effects is still lacking. The present study has sought to investigate the relationship between IF and changes in gene expression. We focused on the liver, which is highly sensitive to metabolic changes due to energy status. Mice were randomly assigned to ad libitum feeding or IF for 16 hours per day or for 24 hours on alternate days for 3 months, after which genome-wide transcriptome analysis of the liver was performed using RNA sequencing. Our findings revealed that IF caused robust transcriptomic changes in the liver that led to a complex array of metabolic changes. We also observed that the IF regimen produced distinct profiles of transcriptomic changes, highlighting the significance of temporally different periods of energy restriction. Our results suggest that IF can regulate metabolism via transcriptomic mechanisms and provide insight into how genetic interactions within the liver might lead to the numerous metabolic benefits of IF.
ABSTRACT
Stroke is the second leading cause of death in the world and a major cause of long-term disability. Recent evidence has provided insight into a newly described inflammatory mechanism that contributes to neuronal and glial cell death, and impaired neurological outcome following ischemic stroke - a form of sterile inflammation involving innate immune complexes termed inflammasomes. It has been established that inflammasome activation following ischemic stroke contributes to neuronal cell death, but little is known about inflammasome function and cell death in activated microglial cells following cerebral ischemia. Microglia are considered the resident immune cells that function as the primary immune defense in the brain. This study has comprehensively investigated the expression and activation of NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes in isolates of microglial cells subjected to simulated ischemic conditions and in the brain following ischemic stroke. Immunoblot analysis from culture media indicated microglial cells release inflammasome components and inflammasome activation-dependent pro-inflammatory cytokines following ischemic conditions. In addition, a functional role for NLRC4 inflammasomes was determined using siRNA knockdown of NLRC4 and pharmacological inhibitors of caspase-1 and -8 to target apoptotic and pyroptotic cell death in BV2 microglial cells under ischemic conditions. In summary, the present study provides evidence that the NLRC4 inflammasome complex mediates the inflammatory response, as well as apoptotic and pyroptotic cell death in microglial cells under in vitro and in vivo ischemic conditions.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Calcium-Binding Proteins/metabolism , Inflammasomes/metabolism , Stroke/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Apoptosis/immunology , Apoptosis Regulatory Proteins/physiology , Brain/metabolism , Brain Ischemia/immunology , Brain Ischemia/physiopathology , Calcium-Binding Proteins/physiology , Caspase 1/metabolism , Cell Death , Inflammasomes/physiology , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neurons/metabolism , Primary Cell Culture , Pyroptosis/immunology , Signal Transduction/physiology , Stroke/immunologyABSTRACT
In the first part of our review, we extensively discuss the different variants of dietary restriction (DR) regimens, as well as its corresponding mechanism(s) and subsequent effects. We also provide a detailed analysis of the different epigenetic mechanisms based on current knowledge. We postulate that DR may represent an environmental intervention that can modulate the epigenomic profile of an individual. It is highly plausible that epigenetic regulation by DR may help explain the asymmetric manifestation of DR effects in different individuals. Additionally, epigenetic modifications via DR may lead to epigenetic programming, providing protection against age-associated diseases, which in turn could lead to reduced morbidity and increased lifespan. In the second part of the review, we summarize recent findings that highlight the epigenomic axis of DR, which provides a better understanding of the mechanisms by which its numerous health benefits are achieved.