Exploring the Promise and Challenges of Artificial Intelligence in Biomedical Research and Clinical Practice.

Artificial intelligence (AI) is poised to revolutionize how science, and biomedical research in particular, are done. With AI, problem solving and complex tasks using massive data sets can be performed at a much higher rate and dimensionality level compared to humans. With the ability to handle huge data sets and self-learn, AI is already being exploited in drug design, drug repurposing, toxicology, and material identification. AI could also be used in both basic and clinical research in study design, defining outcomes, analyzing data, interpreting findings, and even identifying the most appropriate areas of investigation and funding sources. State-of-the-art AI-based large language models (LLM), such as ChatGPT and Perplexity, are positioned to change forever how science is communicated and how scientists interact with one another and their profession, including post-publication appraisal and critique. Like all revolutions, upheaval will follow and not all outcomes can be predicted, necessitating guardrails at the onset, especially to minimize the untoward impact of the many drawbacks of LLMs, which include lack of confidentiality, risk of hallucinations, and propagation of mainstream albeit potentially mistaken opinions and perspectives. In this review, we highlight areas of biomedical research that are already being reshaped by AI and how AI is likely to impact it further in the near future. We discuss the potential benefits of AI in biomedical research and address possible risks, some surrounding the creative process, that warrant further reflection.

Correction: Noureddine et al. Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives. Int. J. Mol. Sci. 2020, 21, 4268.

The authors would like to make the following correction to the publication dealing with Reference #3 [...].

Central role for BRAF in cardiac hypertrophy: rethinking the pathological-physiological divide.

The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hypertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to define the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular cardiac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated physiological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the 'RAF paradox'. Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex- and context-dependent manner.

FTIR Analysis of Renal Tissue for the Assessment of Hypertensive Organ Damage and proANP31-67 Treatment.

The kidneys are one of the main end organs targeted by hypertensive disease. Although the central role of the kidneys in the regulation of high blood pressure has been long recognized, the detailed mechanisms behind the pathophysiology of renal damage in hypertension remain a matter of investigation. Early renal biochemical alterations due to salt-induced hypertension in Dahl/salt-sensitive rats were monitored by Fourier-Transform Infrared (FTIR) micro-imaging. Furthermore, FTIR was used to investigate the effects of proANP31-67, a linear fragment of pro-atrial natriuretic peptide, on the renal tissue of hypertensive rats. Different hypertension-induced alterations were detected in the renal parenchyma and blood vessels by the combination of FTIR imaging and principal component analysis on specific spectral regions. Changes in amino acids and protein contents observed in renal blood vessels were independent of altered lipid, carbohydrate, and glycoprotein contents in the renal parenchyma. FTIR micro-imaging was found to be a reliable tool for monitoring the remarkable heterogeneity of kidney tissue and its hypertension-induced alterations. In addition, FTIR detected a significant reduction in these hypertension-induced alterations in the kidneys of proANP31-67-treated rats, further indicating the high sensitivity of this cutting-edge imaging modality and the beneficial effects of this novel medication on the kidneys.

What Role do Mitochondria Have in Diastolic Dysfunction? Implications for Diabetic Cardiomyopathy and Heart Failure With Preserved Ejection Function.

ABSTRACT: Diastolic dysfunction is common to both diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). Although commonly attributed to increased fibrosis, alterations in mitochondrial function and associated Ca2+ handling may contribute to impaired cardiac function. With mitochondrial dysfunction, increased reactive oxygen species (ROS), inflammation, and decreased adenosine triphosphate/adenosine diphosphate ratio may lead to increased extracellular matrix and diminished contractile relaxation. In this article, we discuss recent research implicating deficient mitochondria-associated endoplasmic reticulum membranes (MAMs) as it relates to impaired metabolic function and what role that may have in diastolic dysfunction in diabetic cardiomyopathy. The contribution of mitochondrial dysfunction to diastolic dysfunction in HFpEF is less established, but equally credible based on preclinical studies. However, there are notable differences between diabetic cardiomyopathy and HFpEF. Recent evidence implicates impaired endoplasmic reticulum signaling, in particular the unfolded protein response (UPR), in the pathogenesis of HFpEF. With HFpEF, enhanced pressure on the mitochondrial "gas pedal" because of increased cytosolic Ca2+ may perturb mitochondrial homeostasis. For diabetic cardiomyopathy and HFpEF, a better understanding of how altered cellular ion and redox status affect mitochondrial function is needed. Finally, we discuss the implications that mitochondrial dysfunction may have in devising novel therapeutic strategies for diabetic cardiomyopathy and HFpEF.

Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate.

Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei-mitochondria crosstalk with in utero stress awaits further investigation.

The Angiotensin II Type 1(AT1) Receptor and Cardiac Hypertrophy: Did We Have It Wrong All Along?

ABSTRACT: An ongoing issue in cardiac pharmacology is whether angiotensin II has direct growth promoting effects on the heart via the angiotensin II type 1 (AT1) receptor. This question has relevance for whether angiotensin-converting enzyme inhibitors and AT1 receptor blockers offer additional benefit in preventing adverse cardiac remodeling in hypertension. In a recent study, 2 strains of mice were infused with angiotensin II. In both, AT1 receptors were deleted in the heart and conduit vessels, but in one, AT1 receptors were also deleted in resistance vessels. Angiotensin II caused hypertrophy and hypertension in the strain lacking AT1 receptors in the heart and conduit vessels, but not in the strain without AT1 receptors in resistance vessels. This finding supports the conclusion that blood pressure is more important in determining cardiac hypertrophy than direct AT1 activation by angiotensin II, when the two are rapidly and simultaneously introduced. Surprisingly, mice with no cardiac AT1 receptor expression developed ventricular dilation and eccentric hypertrophy with pressure overload, in contrast to wild type mice that exhibited concentric hypertrophy, suggesting that cardiac AT1 receptors protect against high blood pressure. This interpretation revives issues related to ß-arrestin-biased signaling and mechanosensitivity of AT1 receptors. Synthetic nanobodies, which are based on the variable regions of camelid-derived heavy chain-only antibodies, could be applied to explore the therapeutic potential of exploiting different activation states of AT1 under stress conditions, such as hypertension and heart failure. At the very least, this experimental approach is likely to reveal new facets of AT1 receptor signaling in the heart.

Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives.

The effects of the renin-angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood-brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1-7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1-7)/Mas axis constitutes a protective arm of RAS on the blood-brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

Temporal cardiac remodeling post-myocardial infarction: dynamics and prognostic implications in personalized medicine.

Despite dramatic improvements in short-term mortality rates following myocardial infarction (MI), long-term survival for MI patients who progress to heart failure remains poor. MI occurs when the left ventricle (LV) is deprived of oxygen for a sufficient period of time to induce irreversible necrosis of the myocardium. The LV response to MI involves significant tissue, cellular, and molecular level modifications, as well as substantial hemodynamic changes that feedback negatively to amplify the response. Inflammation to remove necrotic myocytes and fibroblast activation to form a scar are key wound healing responses that are highly variable across individuals. Few biomarkers of early remodeling stages are currently clinically adopted. The discovery of underlying pathophysiological mechanisms and associated novel biomarkers has the potential of improving prognostic capability and therapeutic monitoring. Combining these biomarkers with other prominent ones could constitute a powerful diagnostic and prognostic tool that directly reflects the pathophysiological remodeling of the LV. Understanding temporal remodeling at the tissue, cellular, and molecular level and its link to a well-defined set of biomarkers at early stages post-MI is a prerequisite for improving personalized care and devising more successful therapeutic interventions. Here we summarize the integral mechanisms that occur during early cardiac remodeling in the post-MI setting and highlight the most prominent biomarkers for assessing disease progression.

Emerging importance of chemokine receptor CXCR3 and its ligands in cardiovascular diseases.

The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodelling. The observation that several of the above-mentioned chemokines exert biological actions independent of CXCR3 provides both opportunities and challenges for developing effective drug strategies. In this review, we provide evidence to support our contention that CXCR3 and its ligands actively participate in the development and progression of CVDs, and may additionally have utility as diagnostic and prognostic biomarkers.

Update on the Protective Role of Regulatory T Cells in Myocardial Infarction: A Promising Therapy to Repair the Heart.

Myocardial infarction (MI) remains one of the leading causes of heart failure development and death worldwide. To date, interventional and pharmacological therapies are effective in reducing the onset of heart failure and promoting survival. However, progressive maladaptive remodeling post-MI persists in a large fraction of patients resulting in poor prognosis. Immune cell responses and an inflammatory environment largely contribute to adverse cardiac remodeling post-MI. CD4FOXP3 regulatory T cells (Tregs) are known for their immunosuppressive capacity and have been successfully implemented in multiple preclinical studies of permanent and ischemia-reperfusion MI. In this review, we highlight the important cardioprotective role of Tregs at the cardiac tissue, cellular, and molecular level, as well as the most prominent pharmacological venues that could be used to exploit Tregs as a novel therapeutic intervention to lessen myocardial injury post-MI.

Diurnal rhythms of serum and plasma cytokine profiles in healthy elderly individuals assessed using membrane based multiplexed immunoassay.

BACKGROUND: Recent clinical studies suggest that inflammatory mediators have huge potential in individualized therapy and in efficacy screening and can be utilized as biomarkers for a plethora of pathological conditions. The standard approach for detecting and measuring these inflammatory mediators is via blood samples. Nevertheless, there is no scientific report providing solid evidence on the most suitable blood compartment that will give the optimal inflammatory mediator measurement, or regarding the diurnal variation of circulating mediators. In this study, we present the biological variability of circulating cytokines and chemokines from healthy individuals (mean age 59 years) assessed by a novel membrane-based assay. METHODS: Fifteen males and an equal number of females (all above 50 years) with no known inflammatory condition were selected. Through a planar method, named Proteome Profiler™, improved with fluorescence readout into a semi-quantitative multiplex assay, a screening of 36 inflammatory mediators was performed in serum and plasma of morning and afternoon blood withdrawals. RESULTS: The multiplex analysis revealed that the physiological variability of several circulating inflammatory mediators was relatively small within a cohort of 30 healthy aging subjects. There was no substantial gender effect in the inflammatory mediator profile. On the contrary, most of the cytokine/chemokine values measured in the afternoon collection were found to be higher compared to the morning ones, particularly in plasma. CONCLUSIONS: In this study we provide evidence that circulating cytokine and chemokine levels of healthy individuals are elevated when blood is sampled in the afternoon compared to the morning, as influenced by the circulating cortisol levels. Furthermore, we report significant differences between cytokine/chemokine levels measured in serum and plasma. Our results provide essential information for future studies that will focus on examining circulating inflammatory mediator differences between healthy and diseased individuals.

The circular relationship between matrix metalloproteinase-9 and inflammation following myocardial infarction.

Matrix metalloproteinase-9 (MMP-9) regulates remodeling of the left ventricle after myocardial infarction (MI) and is tightly linked to the inflammatory response. The inflammatory response serves to recruit leukocytes as part of the wound healing reaction to the MI injury, and infiltrated leukocytes produce cytokines and chemokines that stimulate MMP-9 production and release. In turn, MMP-9 proteolyzes cytokines and chemokines. Although in most cases, MMP-9 cleavage of the cytokine or chemokine substrate serves to increase activity, there are cases where cleavage results in reduced activity. Global MMP-9 deletion in mouse MI models has proven beneficial, suggesting inhibition of some aspects of MMP-9 activity may be valuable for clinical use. At the same time, overexpression of MMP-9 in macrophages has also proven beneficial, indicating that we still do not fully understand the complexity of MMP-9 mechanisms of action. In this review, we summarize the cycle of MMP-9 effects on cytokine production and cleavage to regulate leukocyte functions. Although we use MI as the example process, similar events occur in other inflammatory and wound healing conditions.

Improving membrane based multiplex immunoassays for semi-quantitative detection of multiple cytokines in a single sample.

BACKGROUND: Inflammatory mediators can serve as biomarkers for the monitoring of the disease progression or prognosis in many conditions. In the present study we introduce an adaptation of a membrane-based technique in which the level of up to 40 cytokines and chemokines can be determined in both human and rodent blood in a semi-quantitative way. The planar assay was modified using the LI-COR (R) detection system (fluorescence based) rather than chemiluminescence and semi-quantitative outcomes were achieved by normalizing the outcomes using the automated exposure settings of the Odyssey readout device. The results were compared to the gold standard assay, namely ELISA. RESULTS: The improved planar assay allowed the detection of a considerably higher number of analytes (n = 30 and n = 5 for fluorescent and chemiluminescent detection, respectively). The improved planar method showed high sensitivity up to 17 pg/ml and a linear correlation of the normalized fluorescence intensity with the results from the ELISA (r = 0.91). CONCLUSIONS: The results show that the membrane-based technique is a semi-quantitative assay that correlates satisfactorily to the gold standard when enhanced by the use of fluorescence and subsequent semi-quantitative analysis. This promising technique can be used to investigate inflammatory profiles in multiple conditions, particularly in studies with constraints in sample sizes and/or budget.

Caloric Restriction Rejuvenates Skeletal Muscle Growth in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major clinical problem, with limited treatments. HFpEF is characterized by a distinct, but poorly understood, skeletal muscle pathology, which could offer an alternative therapeutic target. In a rat model, we identified impaired myonuclear accretion as a mechanism for low myofiber growth in HFpEF following resistance exercise. Acute caloric restriction rescued skeletal muscle pathology in HFpEF, whereas cardiac therapies had no effect. Mechanisms regulating myonuclear accretion were dysregulated in patients with HFpEF. Overall, these findings may have widespread implications in HFpEF, indicating combined dietary with exercise interventions as a beneficial approach to overcome skeletal muscle pathology.

Role of ranolazine in heart failure: From cellular to clinic perspective.

Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review.

Insights into the modulation of the interferon response and NAD+ in the context of COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in dramatic worldwide mortality. Along with developing vaccines, the medical profession is exploring new strategies to curb this pandemic. A better understanding of the molecular consequences of SARS-CoV-2 cellular infection could lead to more effective and safer treatments. This review discusses the potential underlying impact of SARS-CoV-2 in modulating interferon (IFN) secretion and in causing mitochondrial NAD+ depletion that could be directly linked to COVID-19's deadly manifestations. What is known or surmised about an imbalanced innate immune response and mitochondrial dysfunction post-SARS-CoV-2 infection, and the potential benefits of well-timed IFN treatments and NAD+ boosting therapies in the context of the COVID-19 pandemic are discussed.

Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats.

Heart failure with preserved ejection fraction (HFpEF) remains a medical anomaly that baffles researchers and physicians alike. The overall phenotypical changes of diastolic function and left ventricular hypertrophy observed in HFpEF are definable; however, the metabolic and molecular alterations that ultimately produce these changes are not well established. Comorbidities such as obesity, hypertension, and diabetes, as well as general aging, play crucial roles in its development and progression. Various animal models have recently been developed to better understand the pathophysiological and metabolic developments in HFpEF and to illuminate novel avenues for pharmacotherapy. These models include multi-hit rodents and feline aortic constriction animals. Recently, genomic, proteomic, and metabolomic approaches have been used to define altered signaling pathways in the heart associated with HFpEF, including those involved in inflammation, cGMP-related, Ca2+ handling, mitochondrial respiration, and the unfolded protein response in endoplasmic reticulum stress. This article aims to present an overview of what has been learnt by these studies, focusing mainly on the findings in common while highlighting unresolved issues. The knowledge gained from these research models will not simply be of benefit for treating HFpEF but will undoubtedly provide new insights into the mechanisms by which the heart deals with external stresses and how the processes involved can fail.

Early cardiac-chamber-specific fingerprints in heart failure with preserved ejection fraction detected by FTIR and Raman spectroscopic techniques.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is a matter of investigation and its diagnosis remains challenging. Although the mechanisms that are responsible for the development of HFpEF are not fully understood, it is well known that nearly 80% of patients with HFpEF have concomitant hypertension. We investigated whether early biochemical alterations were detectable during HFpEF progression in salt-induced hypertensive rats, using Fourier-transformed infrared (FTIR) and Raman spectroscopic techniques as a new diagnostic approach. Greater protein content and, specifically, greater collagen deposition were observed in the left atrium and right ventricle of hypertensive rats, together with altered metabolism of myocytes. Additionally, Raman spectra indicated a conformational change, or different degree of phosphorylation/methylation, in tyrosine-rich proteins. A correlation was found between tyrosine content and cardiac fibrosis of both right and left ventricles. Microcalcifications were detected in the left and right atria of control animals, with a progressive augmentation from six to 22 weeks. A further increase occurred in the left ventricle and right atrium of 22-week salt-fed animals, and a positive correlation was shown between the mineral deposits and the cardiac size of the left ventricle. Overall, FTIR and Raman techniques proved to be sensitive to early biochemical changes in HFpEF and preceded clinical humoral and imaging markers.

Atrial Natriuretic Peptide31-67: A Novel Therapeutic Factor for Cardiovascular Diseases.

The characterization of the cardiac hormone atrial natriuretic peptide (ANP9 9 - 1 26), synthesized and secreted predominantly by atrial myocytes under stimulation by mechanical stretch, has established the heart as an endocrine organ with potent natriuretic, diuretic, and vasodilating actions. Three additional distinct polypeptides resulting from proteolytic cleavage of proANP have been identified in the circulation in humans. The mid-sequence proANP fragment 31-67 (also known as proANP3 1 - 6 7) has unique potent and prolonged diuretic and natriuretic properties. In this review, we report the main effects of this circulating hormone in different tissues and organs, and its mechanisms of actions. We further highlight recent evidence on the cardiorenal protective actions of chronic supplementation of synthetic proANP3 1 - 6 7 in preclinical models of cardiorenal disease. Finally, we evaluate the use of proANP3 1 - 6 7 as a new therapeutic strategy to repair end-organ damage secondary to hypertension, diabetes mellitus, renal diseases, obesity, heart failure, and other morbidities that can lead to impaired cardiac function and structure.