Heme Oxygenase-1, Cardiac Senescence, and Myocardial Infarction: A Critical Review of the Triptych.

PURPOSE: Heme oxygenase-1 (HO-1) is a crucial enzyme in heme metabolism, facilitating the breakdown of heme into biliverdin, carbon monoxide, and free iron. Renowned for its potent cytoprotective properties, HO-1 showcases notable antioxidant, anti-inflammatory, and anti-apoptotic effects. In this review, the authors aim to explore the profound impact of HO-1 on cardiac senescence and its potential implications in myocardial infarction (MI). RESULTS: Recent research has unveiled the intricate role of HO-1 in cellular senescence, characterized by irreversible growth arrest and functional decline. Notably, cardiac senescence has emerged as a pivotal factor in the development of various cardiovascular conditions, including MI. Notably, cardiac senescence has emerged as an important factor in the development of various cardiovascular conditions, including myocardial infarction (MI). The accumulation of senescent cells, spanning vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, and progenitor cells, poses a significant risk for cardiovascular diseases such as vascular aging, atherosclerosis, myocardial infarction, and ventricular remodeling. Inhibition of cardiomyocyte senescence not only reduces senescence-associated inflammation but also impacts other myocardial lineages, hinting at a broader mechanism of propagation in pathological remodeling. HO-1 has been shown to improve heart function and mitigate cardiomyocyte senescence induced by ischemic injury and aging. Furthermore, HO-1 induction has been found to alleviate H2O2-induced cardiomyocyte senescence. As we grow in our understanding of antiproliferative, antiangiogenic, anti-aging, and vascular effects of HO-1, we see the potential to exploit potential links between individual susceptibility to cardiac senescence and myocardial infarction. CONCLUSIONS: This review investigates strategies for upregulating HO-1, including gene targeting and pharmacological agents, as potential therapeutic approaches. By synthesizing compelling evidence from diverse experimental models and clinical investigations, this study elucidates the therapeutic potential of targeting HO-1 as an innovative strategy to mitigate cardiac senescence and improve outcomes in myocardial infarction, emphasizing the need for further research in this field.

Bioprinting in cardiovascular medicine: Possibilities, challenges, and future perspectives for low and middle-income countries.

Cardiovascular diseases (CVD) stemming from various factors significantly impact the quality of life (QoL) and are prevalent with high mortality rates in both developed and developing countries. In cases where pharmacotherapy proves insufficient and end-stage disease ensues, a heart transplant/surgical repair becomes the only feasible treatment option. However, challenges such as a limited supply of heart donors, complications associated with rejection, and issues related to medication compliance introduce an additional burden to healthcare services and adversely affect patient outcomes. The emergence of bioprinting has facilitated advancements in creating structures, including ventricles, valves, and blood vessels. Notably, the development of myocardial/cardiac patches through bioprinting has offered a promising avenue for revascularizing, strengthening, and regenerating ventricles. Employment loss in developing countries as a circumstance of disability or death can severely impact a family's well-being and means for sustainable living. Innovations by means of life sustaining treatment options can provide hope for the impoverished and help reduce disability burden on the economy of low- to middle-income countries (LMICs). Such developments can have a significant impact that can last for generations, especially in developing countries. In this review, the authors delve into various types of bioprinting techniques, exploring their possibilities, challenges, and potential future applications in treating various end-stage cardiovascular conditions in LMICs.

Protocol for preparing Drosophila genomic DNA to create chromosome-level de novo genome assemblies.

De novo genome assemblies are common tools for examining novel biological phenomena in non-model organisms. Here, we present a protocol for preparing Drosophila genomic DNA to create chromosome-level de novo genome assemblies. We describe steps for high-molecular-weight DNA preparation with phenol or Genomic-tips, quality control, long-read nanopore sequencing, short-read DNA library preparation, and sequencing. We then detail procedures of genome assembly, annotation, and assessment that can be used for downstream comparison and functional analysis. For complete details on the use and execution of this protocol, please refer to Sperling et al.1.

Unusual case of bullous emphysema with superimposed pneumonia.

Bullous emphysema is a chronic obstructive pulmonary disease (COPD) that results from chronic inflammation of the lung parenchyma leading to alveolar destruction. Etiology includes tobacco smoking and alpha-1 antitrypsin deficiency. In this article, we present a rare case of bullous emphysema in a nonsmoker with no genetic predisposition or social risk factors presenting with productive cough, fatigue, and shortness of breath. The patient was diagnosed with bullous emphysema with superimposed pneumonia based on clinical and radiological findings. The patients acute complaints were treated successfully with antibiotics, supplemental oxygen, systemic steroids, and, nebulizer treatments. With this case report the authors highlight an unusual presentation of pneumonia in a patient with underlying bullous emphysema. Environmental exposure is often overlooked and the outcomes cannot be turned to favor without a comprehensive approach in patient management from history and physical to deciding the right treatment and follow-up protocols.

Social determinants of health and its impact on cardiovascular disease in underserved populations: A critical review.

In the United States, a patient succumbs to cardiovascular disease (CVD) every 33 seconds and costs the healthcare system close to $240 billion dollars annually. Social determinants of health (SDOH) are key factors responsible in structuring the well-being of individuals and communities. It significantly influences health outcomes and is reliant on several factors such as economic stability, education, healthcare access, community composition, and governmental policies. This review explores the impact of SDOH on the escalating global burden of CVD and identifies potential modifiable risk factors that contribute to acute coronary syndrome (ACS) among underserved communities. In addition, it also addresses the necessity for interventions to narrow healthcare related disparities ensuring improvement in CVD outcomes in this subgroup of population.

Marijuana-induced ST-elevation myocardial infarction in adolescents and young adults: A case report and comprehensive review of literature.

As per the Centers for Disease Control and Prevention (CDC), the incidence of myocardial infarction (MI) is reported to be 805,000 cases annually in the United States (US). Although commonly occurring in elderly individuals with underlying cardiovascular comorbidities or younger generations with familial predispositions serving as risk factors, it is extremely rare for an isolated event to occur in teenagers with a history of marijuana use. In this article, we report a rare case of ST-elevation myocardial infarction (STEMI) in a 19-year-old male with no past medical history that was attributed to marijuana use. This case report and review of literature depict a potential association between marijuana use and STEMI. We also highlight potential clinical implications to aid healthcare professionals in making an early diagnosis and achieving a timely management strategy.

Recurrent syncopal episodes in a pregnant patient with neurocysticercosis.

Neurocysticercosis (NCC) is the most common parasitic infection of the nervous system and acquired epilepsy in low-resource settings due to the pork tapeworm, Taenia solium. Humans contract the intestinal infection of the adult tapeworm (taeniasis) through the fecal-oral route after consuming undercooked food, particularly pork or water, contaminated with tapeworm eggs. When the larvae invades the central nervous system (CNS), the infection causes NCC, which often manifests as late-onset seizures, chronic headaches, and intracranial hypertension. We describe a 31-year-old Hispanic multigravida woman from Guatemala, at 33 weeks of gestation, who presented with multiple syncopal and hypotensive episodes prompting a Computed tomography (CT) image of the head revealing multiple small cerebral calcifications indicating NCC. In this article, we highlight the significance of early symptom recognition and diagnostic workup for NCC in areas with diverse immigrant populations. We also discuss the epidemiology, clinical manifestations, and current treatment modalities available for NCC.

A genetic basis for facultative parthenogenesis in Drosophila.

Facultative parthenogenesis enables sexually reproducing organisms to switch between sexual and asexual parthenogenetic reproduction. To gain insights into this phenomenon, we sequenced the genomes of sexually reproducing and parthenogenetic strains of Drosophila mercatorum and identified differences in the gene expression in their eggs. We then tested whether manipulating the expression of candidate gene homologs identified in Drosophila mercatorum could lead to facultative parthenogenesis in the non-parthenogenetic species Drosophila melanogaster. This identified a polygenic system whereby increased expression of the mitotic protein kinase polo and decreased expression of a desaturase, Desat2, caused facultative parthenogenesis in the non-parthenogenetic species that was enhanced by increased expression of Myc. The genetically induced parthenogenetic Drosophila melanogaster eggs exhibit de novo centrosome formation, fusion of the meiotic products, and the onset of development to generate predominantly triploid offspring. Thus, we demonstrate a genetic basis for sporadic facultative parthenogenesis in an animal.

Ocular and Palpebral Manifestations of Facial Palsy: An Epidemiologic Descriptive Study.

Purpose: We describe the ocular and periocular clinical features in patients with a facial palsy diagnosis of any etiology and to report the demographics, relevant medical history and treatment modalities in these patients. Patients and Methods: Retrospective and descriptive observational study. A total of 60 patients with a facial palsy diagnosis in the last 5 years were recruited from an ophthalmological clinic in northeastern Mexico. Demographic data, such as age, sex, disease evolution and etiology, visual acuity, ocular symptoms and ocular and periocular clinical features were obtained. Personal history of previous ophthalmologic surgery, as well as ocular and systemic diseases, were also recorded. Finally, a comparative analysis was done to determine association between signs, symptoms and treatment modalities. Results: A prevalence of 0.14% was reported, 56.7% of patients were female, and mean age of presentation was 55.63±17.2 years. 76.7% of facial palsy was idiopathic in origin, followed by vascular disease in 8.30% and iatrogenic in 6.70%. 40% of patients had a history of arterial hypertension, 36.3% were diabetic, and 6.70% had cerebrovascular disease. Conclusion: Early diagnosis of facial palsy is crucial in establishing an effective treatment plan and avoiding complications. The impact of this disease in patients' quality of life cannot be overlooked, and steps should be taken to address the different impairments that this ailment entails.

Exploring the Potential of Broadly Neutralizing Antibodies for Treating SARS-CoV-2 Variants of Global Concern in 2023: A Comprehensive Clinical Review.

In the aftermath of the coronavirus disease 2019 (COVID-19) pandemic, the world is still seeing outbreaks of COVID-19 infections as of 2023, especially in populations that have been adequately vaccinated. This situation across the globe gives rise to important questions regarding the efficacy of current treatments and the real rate of mutations in the COVID-19 virus itself which can make the currently available treatments and vaccines obsolete. We have tried to answer a few of those questions and put forth some new questions of our own. Our efforts in this paper were directed towards understanding the utilization of broadly neutralizing antibodies as a treatment for COVID-19 infection with a particular focus on the Omicron variant and other newer variants. We gathered our data from three major databases: PubMed, Google Scholar, and Cochrane Central Register of Controlled Trials (CENTRAL). We have screened 7070 studies from inception till March 5, 2023, and gathered 63 articles that were relevant to the topic of interest. Based on the existing medical literature regarding the topic of interest and also based on our own personal and clinical experience treating COVID-19 patients across the multiple waves in the United States and India since the beginning of the pandemic, we have concluded that broad neutralizing antibodies could be an effective option for treatment and prophylaxis for current and future outbreaks of COVID-19 including the Omicron variant and newer variants. Further research, including clinical trials, is required to tailor optimal dosages, prevent adverse reactions/side effects, and develop treatment strategies.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) in Cardiovascular Disease: A Comprehensive Clinical Review on Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the most important causes of heart failure in developed and developing countries. Currently, most medical interventions in the treatment of DCM are mainly focused on mitigating the progression of the disease and controlling the symptoms. The vast majority of patients who survive till the late stages of the disease require cardiac transplantation; this is exactly why we need novel therapeutic interventions and hopefully treatments that can reverse the clinical cardiac deterioration in patients with DCM. Clustered regularly interspaced short palindromic repeats (CRISPR) technology is a novel therapeutic intervention with such capacity; it can help us edit the genome of patients with genetic etiology for DCM and potentially cure them permanently. This review provides an overview of studies investigating CRISPR-based gene editing in DCM, including the use of CRISPR in DCM disease models, phenotypic screening, and genotype-specific precision therapies. The review discusses the outcomes of these studies and highlights the potential benefits of CRISPR in developing novel genotype-agnostic therapeutic strategies for the genetic causes of DCM. The databases we used to extract relevant literature include PubMed, Google Scholar, and Cochrane Central. We used the Medical Subject Heading (MeSH) strategy for our literature search in PubMed and relevant search keywords for other databases. We screened all the relevant articles from inception till February 22, 2023. We retained 74 research articles after carefully reviewing each of them. We concluded that CRISPR gene editing has shown promise in developing precise and genotype-specific therapeutic strategies for DCM, but there are challenges and limitations, such as delivering CRISPR-Cas9 to human cardiomyocytes and the potential for unintended gene targeting. This study represents a turning point in our understanding of the mechanisms underlying DCM and paves the way for further investigation into the application of genomic editing for identifying novel therapeutic targets. This study can also act as a potential framework for novel therapeutic interventions in other genetic cardiovascular diseases.

Spontaneous atraumatic heparin-induced hemarthrosis in a patient treated for non-ST-elevation myocardial infarction.

Hemarthrosis secondary to heparin use is a scarce event, especially in patients with no underlying thrombophilia or platelet disorders. Although previously associated with thrombophilia, platelet disorders, or secondary to fibrinolytic therapy, to date, there are very few reported cases in contemporary literature for heparin-induced hemarthrosis. In this article, we report a case of left shoulder joint inferior subluxation secondary to heparin-induced hemarthrosis in an 81-year-old male with an extensive cardiac history and multiple comorbidities. This case report depicts a rare event and discusses its clinical implications aiding healthcare professionals in an early diagnosis and timely management.

A novel transposable element-mediated mechanism causes antiviral resistance in Drosophila through truncating the Veneno protein.

Hosts are continually selected to evolve new defenses against an ever-changing array of pathogens. To understand this process, we examined the genetic basis of resistance to the Drosophila A virus in Drosophila melanogaster. In a natural population, we identified a polymorphic transposable element (TE) insertion that was associated with an ∼19,000-fold reduction in viral titers, allowing flies to largely escape the harmful effects of infection by this virulent pathogen. The insertion occurs in the protein-coding sequence of the gene Veneno, which encodes a Tudor domain protein. By mutating Veneno with CRISPR-Cas9 in flies and expressing it in cultured cells, we show that the ancestral allele of the gene has no effect on viral replication. Instead, the TE insertion is a gain-of-function mutation that creates a gene encoding a novel resistance factor. Viral titers remained reduced when we deleted the TE sequence from the transcript, indicating that resistance results from the TE truncating the Veneno protein. This is a novel mechanism of virus resistance and a new way by which TEs can contribute to adaptation.

Drosophila Evolution over Space and Time (DEST): A New Population Genomics Resource.

Drosophila melanogaster is a leading model in population genetics and genomics, and a growing number of whole-genome data sets from natural populations of this species have been published over the last years. A major challenge is the integration of disparate data sets, often generated using different sequencing technologies and bioinformatic pipelines, which hampers our ability to address questions about the evolution of this species. Here we address these issues by developing a bioinformatics pipeline that maps pooled sequencing (Pool-Seq) reads from D. melanogaster to a hologenome consisting of fly and symbiont genomes and estimates allele frequencies using either a heuristic (PoolSNP) or a probabilistic variant caller (SNAPE-pooled). We use this pipeline to generate the largest data repository of genomic data available for D. melanogaster to date, encompassing 271 previously published and unpublished population samples from over 100 locations in >20 countries on four continents. Several of these locations have been sampled at different seasons across multiple years. This data set, which we call Drosophila Evolution over Space and Time (DEST), is coupled with sampling and environmental metadata. A web-based genome browser and web portal provide easy access to the SNP data set. We further provide guidelines on how to use Pool-Seq data for model-based demographic inference. Our aim is to provide this scalable platform as a community resource which can be easily extended via future efforts for an even more extensive cosmopolitan data set. Our resource will enable population geneticists to analyze spatiotemporal genetic patterns and evolutionary dynamics of D. melanogaster populations in unprecedented detail.

Broad geographic sampling reveals the shared basis and environmental correlates of seasonal adaptation in Drosophila.

To advance our understanding of adaptation to temporally varying selection pressures, we identified signatures of seasonal adaptation occurring in parallel among Drosophila melanogaster populations. Specifically, we estimated allele frequencies genome-wide from flies sampled early and late in the growing season from 20 widely dispersed populations. We identified parallel seasonal allele frequency shifts across North America and Europe, demonstrating that seasonal adaptation is a general phenomenon of temperate fly populations. Seasonally fluctuating polymorphisms are enriched in large chromosomal inversions, and we find a broad concordance between seasonal and spatial allele frequency change. The direction of allele frequency change at seasonally variable polymorphisms can be predicted by weather conditions in the weeks prior to sampling, linking the environment and the genomic response to selection. Our results suggest that fluctuating selection is an important evolutionary force affecting patterns of genetic variation in Drosophila.

Common genetic associations between age-related diseases.

Age is a common risk factor in many diseases, but the molecular basis for this relationship is elusive. In this study we identified 4 disease clusters from 116 diseases in the UK Biobank data, defined by their age-of-onset profiles, and found that diseases with the same onset profile are genetically more similar, suggesting a common etiology. This similarity was not explained by disease categories, co-occurrences or disease cause-effect relationships. Two of the four disease clusters had an increased risk of occurrence from age 20 and 40 years respectively. They both showed an association with known aging-related genes, yet differed in functional enrichment and evolutionary profiles. Moreover, they both had age-related expression and methylation changes. We also tested mutation accumulation and antagonistic pleiotropy theories of aging and found support for both.

Activating transcription factor 4-dependent lactate dehydrogenase activation as a protective response to amyloid beta toxicity.

Accumulation of amyloid beta peptides is thought to initiate the pathogenesis of Alzheimer's disease. However, the precise mechanisms mediating their neurotoxicity are unclear. Our microarray analyses show that, in Drosophila models of amyloid beta 42 toxicity, genes involved in the unfolded protein response and metabolic processes are upregulated in brain. Comparison with the brain transcriptome of early-stage Alzheimer's patients revealed a common transcriptional signature, but with generally opposing directions of gene expression changes between flies and humans. Among these differentially regulated genes, lactate dehydrogenase (Ldh) was up-regulated by the greatest degree in amyloid beta 42 flies and the human orthologues (LDHA and LDHB) were down-regulated in patients. Functional analyses revealed that either over-expression or inhibition of Ldh by RNA interference (RNAi) slightly exacerbated climbing defects in both healthy and amyloid beta 42-induced Drosophila. This suggests that metabolic responses to lactate dehydrogenase must be finely-tuned, and that its observed upregulation following amyloid beta 42 production could potentially represent a compensatory protection to maintain pathway homeostasis in this model, with further manipulation leading to detrimental effects. The increased Ldh expression in amyloid beta 42 flies was regulated partially by unfolded protein response signalling, as ATF4 RNAi diminished the transcriptional response and enhanced amyloid beta 42-induced climbing phenotypes. Further functional studies are required to determine whether Ldh upregulation provides compensatory neuroprotection against amyloid beta 42-induced loss of activating transcription factor 4 activity and endoplasmatic reticulum stress. Our study thus reveals dysregulation of lactate dehydrogenase signalling in Drosophila models and patients with Alzheimer's disease, which may lead to a detrimental loss of metabolic homeostasis. Importantly, we observed that down-regulation of ATF4-dependent endoplasmic reticulum-stress signalling in this context appears to prevent Ldh compensation and to exacerbate amyloid beta 42-dependent neuronal toxicity. Our findings, therefore, suggest caution in the use of therapeutic strategies focussed on down-regulation of this pathway for the treatment of Alzheimer's disease, since its natural response to the toxic peptide may induce beneficial neuroprotective effects.

Functional conservation in genes and pathways linking ageing and immunity.

At first glance, longevity and immunity appear to be different traits that have not much in common except the fact that the immune system promotes survival upon pathogenic infection. Substantial evidence however points to a molecularly intertwined relationship between the immune system and ageing. Although this link is well-known throughout the animal kingdom, its genetic basis is complex and still poorly understood. To address this question, we here provide a compilation of all genes concomitantly known to be involved in immunity and ageing in humans and three well-studied model organisms, the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the house mouse Mus musculus. By analysing human orthologs among these species, we identified 7 evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-ß, and Nf-κB pathways that act pleiotropically on ageing and immunity. We review current evidence for these pathways linking immunity and lifespan, and their role in the detrimental dysregulation of the immune system with age, known as immunosenescence. We argue that the phenotypic effects of these pathways are often context-dependent and vary, for example, between tissues, sexes, and types of pathogenic infection. Future research therefore needs to explore a higher temporal, spatial and environmental resolution to fully comprehend the connection between ageing and immunity.

Allelic polymorphism at foxo contributes to local adaptation in Drosophila melanogaster.

The insulin/insulin-like growth factor signalling pathway has been hypothesized as a major determinant of life-history profiles that vary adaptively in natural populations. In Drosophila melanogaster, multiple components of this pathway vary predictably with latitude; this includes foxo, a conserved gene that regulates insulin signalling and has pleiotropic effects on a variety of fitness-associated traits. We hypothesized that allelic variation at foxo contributes to genetic variance for size-related traits that vary adaptively with latitude. We first examined patterns of variation among natural populations along a latitudinal transect in the eastern United States and show that thorax length, wing area, wing loading, and starvation tolerance exhibit significant latitudinal clines for both males and females but that development time does not vary predictably with latitude. We then generated recombinant outbred populations and show that naturally occurring allelic variation at foxo, which exhibits stronger clinality than expected, is associated with the same traits that vary with latitude in the natural populations. Our results suggest that allelic variation at foxo contributes to adaptive patterns of life-history variation in natural populations of this genetic model.

Transposable Element Landscape in Drosophila Populations Selected for Longevity.

Transposable elements (TEs) inflict numerous negative effects on health and fitness as they replicate by integrating into new regions of the host genome. Even though organisms employ powerful mechanisms to demobilize TEs, transposons gradually lose repression during aging. The rising TE activity causes genomic instability and was implicated in age-dependent neurodegenerative diseases, inflammation, and the determination of lifespan. It is therefore conceivable that long-lived individuals have improved TE silencing mechanisms resulting in reduced TE expression relative to their shorter-lived counterparts and fewer genomic insertions. Here, we test this hypothesis by performing the first genome-wide analysis of TE insertions and expression in populations of Drosophila melanogaster selected for longevity through late-life reproduction for 50-170 generations from four independent studies. Contrary to our expectation, TE families were generally more abundant in long-lived populations compared with nonselected controls. Although simulations showed that this was not expected under neutrality, we found little evidence for selection driving TE abundance differences. Additional RNA-seq analysis revealed a tendency for reducing TE expression in selected populations, which might be more important for lifespan than regulating genomic insertions. We further find limited evidence of parallel selection on genes related to TE regulation and transposition. However, telomeric TEs were genomically and transcriptionally more abundant in long-lived flies, suggesting improved telomere maintenance as a promising TE-mediated mechanism for prolonging lifespan. Our results provide a novel viewpoint indicating that reproduction at old age increases the opportunity of TEs to be passed on to the next generation with little impact on longevity.