Organ Level Research Articles

Abstract I001: Long noncoding RNAs at the intersection of cancer pathways

Abstract There are thousands of long noncoding RNAs (lncRNAs) in mammalian genomes. Yet, their functional significance in health and disease states remains poorly understood. We investigate the intersection of lncRNAs and cancer biology. On the one hand, we dissect the molecular and cellular mechanisms by which lncRNAs modulate cancer pathways. On the other hand, we develop mouse models to interrogate the roles of lncRNAs in tumorigenesis at the organismal level. Our work has uncovered insights into the transcriptional regulatory roles of lncRNAs during the cellular response to genotoxic and oncogenic stress. In parallel, we have elucidated roles of lncRNAs as drivers of tumor progression and metastatic dissemination. The combined functional and mechanistic studies have revealed the importance of lncRNAs in cancer and suggest therapeutic approaches to target lncRNAs or their downstream effectors in cancer. Citation Format: Nadya Dimitrova. Long noncoding RNAs at the intersection of cancer pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I001.

Non-targeted N-glycome profiling reveals multiple layers of organ-specific diversity in mice

N-glycosylation is one of the most common protein modifications in eukaryotes, with immense importance at the molecular, cellular, and organismal level. Accurate and reliable N-glycan analysis is essential to obtain a systems-wide understanding of fundamental biological processes. Due to the structural complexity of glycans, their analysis is still highly challenging. Here we make publicly available a consistent N-glycome dataset of 20 different mouse tissues and demonstrate a multimodal data analysis workflow that allows for unprecedented depth and coverage of N-glycome features. This highly scalable, LC-MS/MS data-driven method integrates the automated identification of N-glycan spectra, the application of non-targeted N-glycome profiling strategies and the isomer-sensitive analysis of glycan structures. Our delineation of critical sub-structural determinants and glycan isomers across the mouse N-glycome uncovered tissue-specific glycosylation patterns, the expression of non-canonical N-glycan structures and highlights multiple layers of N-glycome complexity that derive from organ-specific regulations of glycobiological pathways.

Antioxidant Activity of Anthocyanins and Anthocyanidins: A Critical Review

Anthocyanins are the main plant pigments responsible for the color of flowers, fruits, and vegetative organs of many plants, and are applied also as safe food colorants. They are efficient antioxidants. In this review, the reactivity of anthocyanins and their aglycones, anthocyanidins, in the main antioxidant assays, and their reactions with reactive oxygen and nitrogen species, effects of interactions with other compounds and metal ions on the antioxidant activity of anthocyanins and the electrochemical properties of anthocyanins are presented. Numerous cases of attenuation of oxidative stress at the cellular and organismal levels by anthocyanins are cited. The direct and indirect antioxidant action of anthocyanins, the question of the specificity of anthocyanin action in complex extracts, as well as limitations of cellular in vitro assays and biomarkers used for the detection of antioxidant effects of anthocyanins, are critically discussed.

The evolutionary landscape of prokaryotic chromosome/plasmid balance

The balance between chromosomal and plasmid DNAs determines the genomic plasticity of prokaryotes. Natural selections, acting on the level of organisms or plasmids, shape the abundances of plasmid DNAs in prokaryotic genomes. Despite the importance of plasmids in health and engineering, there have been rare systematic attempts to quantitatively model and predict the determinants underlying the strength of different selection forces. Here, we develop a metabolic flux model that describes the intracellular resource competition between chromosomal and plasmid-encoded reactions. By coarse graining, this model predicts a landscape of natural selections on chromosome/plasmid balance, which is featured by the tradeoff between phenotypic and non-phenotypic selection pressures. This landscape is further validated by the observed pattern of plasmid distributions in the vast collection of prokaryotic genomes retrieved from the NCBI database. Our results establish a universal paradigm to understand the prokaryotic chromosome/plasmid interplay and provide insights into the evolutionary origin of plasmid diversity.

Electrophysiological tolerance - a new concept for understanding the electrical stability of the heart.

The coordinated electrical activity of ∼2 billion cardiac cells ensures stability of the heartbeat. Indeed, the remarkably low incidence (<1%) of ventricular arrhythmias in the healthy heart is only possible when the electrical event across this syncytium is closely controlled. In contrast, the diseased myocardium is associated with increased electrophysiological heterogeneity, unstable rhythm, and increased incidence of lethal arrhythmias. But what is the link between cellular and tissue level heterogeneity? Recent research has shown the existence of considerable cellular heterogeneity even in the healthy heart, suggesting that cell-to-cell variability in electrical (e.g. action potential duration) and mechanical performance (e.g. twitch amplitude) is a normal property. This observation has been previously unappreciated because the aggregated function in the form of QT-interval and cardiac output varies <1% on a beat-to-beat basis. This article describes the underlying cellular variability that is tolerated - and perhaps needed - by different regions of the heart for normal function and indicates why this variability is not apparent in function at the chamber and organ level. Thus, in contrast to the current dominant view, this article postulates that heterogeneity is normal and potentially endows various functional benefits. This new view of how the component parts of the heart come together to function also suggests novel mechanisms for cardiac pathologies, namely that dysfunction may emerge from changes in the extent and/or nature of heterogeneity. Once understood, restoring normal forms of heterogeneity could be a novel approach to treatment.

Enhancement of physiology via adaptive transcription.

The enhancement of complex physiological functions such as cognition and exercise performance in healthy individuals represents a challenging goal. Adaptive transcription programs that are naturally activated in animals to mediate cellular plasticity in response to stimulation can be leveraged to enhance physiological function above wild-type levels in young organisms and counteract complex functional decline in aging. In processes such as learning and memory and exercise-dependent muscle remodeling, a relatively small number of molecules such as certain stimulus-responsive transcription factors and immediate early genes coordinate widespread changes in cellular physiology. Adaptive transcription can be targeted by various methods including pharmaceutical compounds and gene transfer technologies. Important problems for leveraging adaptive transcription programs for physiological enhancement include a better understanding of their dynamical organization, more precise methods to influence the underlying molecular components, and the integration of adaptive transcription into multi-scale physiological enhancement concepts.

Plasma proteomics-based organ-specific aging for all-cause mortality and cause-specific mortality: a prospective cohort study.

Individual's aging rates vary across organs. However, there are few methods for assessing aging at organ levels and whether they contribute differently to mortalities remains unknown. We analyzed data from 45,821 adults in the UK Biobank, using plasma proteomics and machine learning to estimate biological ages for 12 major organs. The differences between biological age and chronological age, referred to as "age gaps," were calculated for each organ. Partial correlation analyses were used to assess the association between age gaps and modifiable factors. Adjusted multivariable Cox regression models were applied to examine the association of age gaps with all-cause mortality, cause-specific mortalities, and cancer-specific mortalities. We reveal a complex network of varied associations between multi-organ aging and modifiable factors. All age gaps increase the risk of all-cause mortality by 6-60%. The risk of death varied from 5.54 to 29.18 times depending on the number of aging organs. Cause-specific mortalities are associated with certain organs' aging. For mental diseases mortality, and nervous system mortality, only brain aging exhibited a significant increased risk of HR 2.38 (per SD, 95% CI: 2.06-2.74) and 1.99 (per SD, 95% CI: 1.84-2.16), respectively. Age gaps of stomach were also a specific indicator for gastric cancer. Eventually, we find that an organ's biological age selectively influences the aging of other organ systems. Our study demonstrates that accelerated aging in specific organs increases the risk of mortality from various causes. This provides a potential tool for early identification of at-risk populations, offering a relatively objective method for precision medicine.

Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems.

Aging is a complex process manifesting at molecular, cellular, organ, and organismal levels. It leads to functional decline, disease, and ultimately death, but the relationship between these fundamental biomedical features remains elusive. By applying elastic net regularization to plasma proteome data of over 50,000 human subjects in the UK Biobank and other cohorts, we report interpretable organ-specific and conventional aging models trained on chronological age, mortality, and longitudinal proteome data. These models predict organ/system-specific disease and indicate that men age faster than women in most organs. Accelerated organ aging leads to diseases in these organs, and specific diets, lifestyles, professions, and medications influence organ aging rates. We then identify proteins driving these associations with organ-specific aging. Our analyses reveal that age-related chronic diseases epitomize accelerated organ- and system-specific aging, modifiable through environmental factors, advocating for both universal whole-organism and personalized organ/system-specific anti-aging interventions.

Assessment of Ecosystem Characteristics and Fishery Carbon Sink Potential of Qianxiahu Reservoir Based on Trophic Level and Carbon Content Methods

Optimizing biological carbon sequestration has become a primary strategy in global low-carbon-emission initiatives. Freshwater fisheries in reservoirs play an important role in aquatic biological carbon sequestration. However, a standard method for evaluating the carbon sink capacity of inland fisheries has not been developed. Therefore, this study aimed to assess and compare the carbon sequestration potential of the Qianxiahu Reservoir’s fisheries using the trophic level and mass-balance methodologies. The Ecopath model was employed to determine the trophic levels of aquatic organisms within the Qianxiahu Reservoir ecosystem, with input parameters sourced from in situ surveys and the literature on reservoirs. The model includes 21 functional groups, with trophic levels ranging from 1.000 to 3.281. The key species identified are silver carp, bighead carp, and crucian carp. The indices of Finn’s cycling index (FCI), connectivity index (CI), system omnivory index (SOI), and total primary production/total respiration (TPP/TR) for the Qianxiahu Reservoir are 11.35, 0.27, 0.196, and 1.540, respectively. These values indicate a high degree of material recycling and complex interconnections among functional groups. The fishery carbon sink potential of the Qianxiahu Reservoir, calculated using the trophic level and carbon content methods, yielded values of 261.8362 tons/km2 and 66.6818 tons/km2, respectively. The trophic level method showed a notable increase of 195,1544 tons/km2 compared to the carbon content method, underscoring significant differences in results between the two methods. The study concludes with recommendations for research on methods to assess the carbon sink capacity of freshwater fisheries, aiming to establish a scientific framework for this evaluation.

The CNP analogue vosoritide reduces arrhythmia in diabetic cardiomyopathy via cGMP-dependent PDE2 stimulation on cellular and organ level

Abstract Background Detrimental arrhythmia occurs frequently in patients with diabetic cardiomyopathy (DiabCM), but safe and effective therapies are limited. Diabetes-associated neuropathological alterations increase the sympathetic tone, leading to hyperactivation of β-adrenoceptor-mediated cAMP signalling in cardiomyocytes (CM). Increased activity of deleterious cAMP-dependent kinases causes pro-arrhythmic dysregulation of intracellular Ca2+ homeostasis. Phosphodiesterases (PDE) can reduce cAMP levels. Exceptionally, the cAMP-hydrolysing activity of PDE2 can be cGMP-dependently increased by C-type natriuretic peptide (CNP). Thus, the CNP analogue vosoritide (approved for the treatment of achondroplasia) might mediate this cGMP/cAMP crosstalk, reducing arrhythmia. Purpose Here, we aim to study whether the cGMP-dependent activation of PDE2 by vosoritide (VO) is sufficient to reduce arrhythmia and arrhythmogenic triggers in DiabCM. Methods Diabetes was induced by 5 consecutive injections of streptozotocin (50 mg/kg) in control (WT) mice and mice with a CM-specific PDE2 knockout (KO). All experiments were performed 5 weeks later. Cardiac function was characterised by echocardiography. Primary ventricular CM were isolated to assess protein expression and phosphorylation levels by Western blot (WB) and cAMP levels by ELISA. Patch-clamp and Ca2+ imaging experiments were used to investigate pro-arrhythmic triggers. Arrhythmic events were quantified in ex vivo perfused hearts after ischaemia-reperfusion (I/R) injury. Results Compared to healthy controls, diabetic animals showed impaired systolic function with a ~9 % reduction in ejection fraction. The significant increase in E/E’ ratio by ~34 % indicated a diastolic dysfunction. Interestingly, the cardiac function was further worsened in diabetic PDE2 KO. WB analysis revealed upregulation of the CNP receptor NPR-B and PDE2 in diabetic CM and altered regulation of proteins involved in cAMP-dependent Ca2+ cycling such as protein kinase A, Ca2+/calmodulin-dependent kinase II and phospholamban. Interestingly, VO significantly reduced isoprenaline (Iso)-induced cAMP levels in diabetic CM. The effect of VO was prevented by specific PDE2 inhibition with BAY 60-7550 (BAY). Furthermore, VO was able to reduce the Iso-induced increase in L-type Ca2+ current, whereas BAY or genetic PDE2 deletion counteracted this effect. Accordingly, VO significantly decreased the Iso-triggered Ca2+ spark frequency by ~40 %. Concomitant PDE2 inhibition or PDE2 KO prevented this anti-arrhythmic effect. Finally, ECG analysis revealed that VO clearly reduced arrhythmia development after I/R in ex vivo perfused diabetic hearts via PDE2 activation. Conclusion Our data indicate that vosoritide-induced PDE2 stimulation may attenuate abnormal cardiac Ca2+ cycling and thereby reduce arrhythmia in diabetic hearts. Thus, vosoritide may be repurposed as a novel anti-arrhythmic drug in DiabCM.

Targeting immunosenescence for improved tumor immunotherapy

AbstractTumor immunotherapy has significantly transformed the field of oncology over the past decade. An optimal tumor immunotherapy would ideally elicit robust innate and adaptive immune responses within tumor immune microenvironment (TIME). Unfortunately, immune system experiences functional decline with chronological age, a process termed “immunosenescence,” which contributes to impaired immune responses against pathogens, suboptimal vaccination outcomes, and heightened vulnerability to various diseases, including cancer. In this context, we will elucidate hallmarks and molecular mechanisms underlying immunosenescence, detailing alterations in immunosenescence at molecular, cellular, organ, and disease levels. The role of immunosenescence in tumorigenesis and senescence‐related extracellular matrix (ECM) has also been addressed. Recognizing that immunosenescence is a dynamic process influenced by various factors, we will evaluate treatment strategies targeting hallmarks and molecular mechanisms, as well as methods for immune cell, organ restoration, and present emerging approaches in immunosenescence for tumor immunotherapy. The overarching goal of immunosenescence research is to prevent tumor development, recurrence, and metastasis, ultimately improving patient prognosis. Our review aims to reveal latest advancements and prospective directions in the field of immunosenescence research, offering a theoretical basis for development of practical anti‐immunosenescence and anti‐tumor strategies.

Modulation of blood pressure by dietary potassium and sodium: Sex differences and modeling analysis.

High Na+ intake has been linked to elevations in blood pressure, whereas K+ has the opposite effect. The underlying mechanisms involve complex interactions among renal function, fluid volume, fluid-regulatory hormones, the vasculature, cardiac function, and the autonomic nervous system. These mechanisms are likely moderated by sex, given the known sex differences in blood pressure regulation and the higher prevalence of hypertension in men. The source of these observed sex differences may be traced to organ and tissue levels, given that kidney function, intrarenal renin-angiotensin system components, renal sympathetic nervous activity, and nitric oxide bioavailability all exhibit sex differences. To assess the functional impact of each of these sex differences, we developed sex-specific computational models to simulate whole-body Na+, K+, and fluid homeostasis, and the effects on blood pressure. The models describe the interactions among the renal system, cardiovascular system, gastrointestinal system, renal sympathetic nervous system, and renin-angiotensin-aldosterone system. Model simulations suggest that women's attenuated blood pressure response to hypertensive stimuli, including high Na+ intake, may be largely attributable to the female renal transporter abundance pattern. Additionally, we investigated the causal link between high K+ intake and blood pressure reduction. The models simulate renal response to high K+ intake, including the immediate gastrointestinal feedforward signals to the kidneys to increase K+ excretion, and the longer-term response to decrease proximal fractional Na+ reabsorption and distal K+ reabsorption. With these assumptions, simulations of high K+ intake yielded kaliuresis, natriuresis, and a substantial reduction in blood pressure, even when combined with high Na+ intake.

HIV Protein Nef Induces Cardiomyopathy Through Induction of Bcl2 and p21

HIV-associated cardiovascular diseases remain a leading cause of death in people living with HIV/AIDS (PLWHA). Although antiretroviral drugs suppress the viral load, they fail to remove the virus entirely. HIV-1 Nef protein is known to play a role in viral virulence and HIV latency. Expression of Nef protein can be detected in different organs, including cardiac tissue. Despite the established role of Nef protein in HIV-1 replication, its impact on organ function inside the human body is not clear. To understand the effect of Nef at the organ level, we created a new Nef-transgenic (Nef-TG) mouse that expresses Nef protein in the heart. Our study found that Nef expression caused inhibition of cardiac function and pathological changes in the heart with increased fibrosis, leading to heart failure and early mortality. Further, we found that cellular autophagy is significantly inhibited in the cardiac tissue of Nef-TG mice. Mechanistically, we found that Nef protein causes the accumulation of Bcl2 and Beclin-1 proteins in the tissue, which may affect the cellular autophagy system. Additionally, we found Nef expression causes upregulation of the cellular senescence marker p21 and senescence-associated b-galactosidase expression. Our findings suggest that the Nef-mediated inhibition of autophagy and induction of senescence markers may promote aging in PLWHA. Our mouse model could help us to understand the effect of Nef protein on organ function during latent HIV infection.

Next-Generation Cancer Phenomics: A Transformative Approach to Unraveling Lung Cancer Complexity and Advancing Precision Medicine.

Lung cancer remains one of the leading causes of cancer-related deaths globally, with its complexity driven by intricate and intertwined genetic, epigenetic, and environmental factors. Despite advances in genomics, transcriptomics, and proteomics, understanding the phenotypic diversity of lung cancer has lagged behind. Next-generation phenomics, which integrates high-throughput phenotypic data with multiomics approaches and digital technologies such as artificial intelligence (AI), offers a transformative strategy for unraveling the complexity of lung cancer. This approach leverages advanced imaging, single-cell technologies, and AI to capture dynamic phenotypic variations at cellular, tissue, and whole organism levels and in ways resolved in temporal and spatial contexts. By mapping the high-throughput and spatially and temporally resolved phenotypic profiles onto molecular alterations, next-generation phenomics provides deeper insights into the tumor microenvironment, cancer heterogeneity, and drug efficacy, safety, and resistance mechanisms. Furthermore, integrating phenotypic data with genomic and proteomic networks allows for the identification of novel biomarkers and therapeutic targets in ways informed by biological structure and function, fostering precision medicine in lung cancer treatment. This expert review examines and places into context the current advances in next-generation phenomics and its potential to redefine lung cancer diagnosis, prognosis, and therapy. It highlights the emerging role of AI and machine learning in analyzing complex phenotypic datasets, enabling personalized therapeutic interventions. Ultimately, next-generation phenomics holds the promise of bridging the gap between molecular alterations and clinical and population health outcomes, providing a holistic understanding of lung cancer biology that could revolutionize its management and improve patient survival rates.

A study on the transfer of radionuclides and of the resulting radiation dose assessment for marine organisms on the eastern coast of Yantai city

Oceans are repositories of radionuclides. Radionuclides are transferred through the food chain and cause ionizing radiation hazards for marine organisms. In this study, the transfer characteristics of 226Ra, 40K, 14C, 3H, 137Cs and 90Sr in organisms at different trophic levels in the eastern coast of Yantai city were investigated. The risk of ionizing radiation to organisms was assessed using the ERICA Tool 2.0. The results show no significant changes in the concentration of any of the nuclides in the coastal area compared to the preoperation period of the nuclear power plant. The transfer factor of 137Cs, 40K, 226Ra, 14C, 90Sr and 3H at the different trophic levels of marine organisms were 2.09, 1.29, 1.17, 1.15, 1.06 and 0.74, respectively. The dose rates of ionizing radiation to organisms from six radionuclides ranged from 32.02 nGy·h-1 to 195.49 nGy·h-1 and had a mean value of 102.86 ± 57.30 nGy·h-1. The main artificial radionuclides (14C, 3H, 90Sr, 137Cs) released by nuclear power plants in the study area produced negligible radiation doses to marine organisms. However, other artificial radionuclides present in the effluents of nuclear power plants (99Tc, 110mAg and 131I) as well as other natural radionuclides (includes 210Po, 210Pb, etc) were not included, and further evaluation of these is recommended.

Multilevel analysis of the central-peripheral-target organ pathway: contributing to recovery after peripheral nerve injury.

Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities. Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites, neglecting multilevel pathological analysis of the overall nervous system and target organs. This has led to restrictions on current therapeutic approaches. In this paper, we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective, covering the central nervous system, peripheral nervous system, and target organs. After peripheral nerve injury, the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves; changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord. The nerve will undergo axonal regeneration, activation of Schwann cells, inflammatory response, and vascular system regeneration at the injury site. Corresponding damage to target organs can occur, including skeletal muscle atrophy and sensory receptor disruption. We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury. The main current treatments are conducted passively and include physical factor rehabilitation, pharmacological treatments, cell-based therapies, and physical exercise. However, most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway. Therefore, we should further explore multilevel treatment options that produce effective, long-lasting results, perhaps requiring a combination of passive (traditional) and active (novel) treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.

Multifaceted roles of TCP transcription factors in fate determination.

Fate determination is indispensable for the accurate shaping and specialization of plant organs, a process critical to the structural and functional diversity in plant kingdom. The TEOSINTE BRANCHED 1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) family of transcription factors has been recognized for its significant contributions to plant organogenesis and morphogenesis. Recent research has shed light on the pivotal roles that TCPs play in fate determination. In this review, we delve into the current understanding of TCP functions, emphasizing their critical influence on fate determination from the organelle to the cell and organ levels. We also consolidate the molecular mechanisms through which TCPs exert their regulatory effects on fate determination. Additionally, we highlight intriguing points of TCPs that warrant further exploration in future research endeavors.

CONCEPTUAL APPROACHES TO THE DIAGNOSIS AND TREATMENT OF PENETRATING GUNSHOT WOUNDS OF THE ABDOMEN WITH DAMAGE TO THE PANCREAS

Summary. The goal is to determine the main directions of the concept of diagnosis and treatment of penetrating gunshot wounds of the abdomen with damage to the pancreas. Materials and methods. A retrospective analysis of the medical records of inpatient patients treated in the VMC of the Northern region, who received combat trauma of the pancreas during the war in Ukraine, was conducted. All the wounded were examined, complaints, medical history were studied, general clinical blood and urine tests were performed, biochemical analysis of blood and abdominal secretions, ultrasound examination of the abdomen and pleural cavity, radiographic examinations of the chest and abdomen, multispiral computed tomography of the chest and abdomen with contrast and without, video endoscopic methods, X-ray spectral and X-ray structural analysis of secretions from the abdomen and pancreatic tissues, electron microscopy, world microscopy, immunohistochemistry, mathematical and statistical methods. The results. The diagnostic component of the concept is implemented through the study of complaint data, anamnesis, local examination, laboratory, instrumental, hardware, histological and immunohistochemical studies. The therapeutic component, which combines conservative and operative measures depending on the patient’s geodynamic stability, is aimed at correcting hemodynamic disorders and influencing the four directions of the conceptual model of treatment of penetrating gunshot wounds to the abdomen with pancreatic damage. It is mandatory to study the foreign bodies of firearm origin that injured the pancreas and the possibilities of modern magnetic surgical instruments for the removal of ferromagnetic foreign bodies. The examination and control of treatment carried out covers research at the atomic and molecular level, at the subcellular level, at the cellular and tissue level, at the organ and clinical levels. All these studies are implemented within the framework of clinical and experimental research design with data analysis using mathematical and statistical methods. Conclusions. Conceptual approaches to the diagnosis and treatment of penetrating gunshot wounds to the abdomen with damage to the pancreas are based on a systematic analysis. The conceptual model is based on the following areas: localization of pancreatic injury, presence or absence of pancreatic duct injury, severity of pancreatic injury according to AAST, presence of combined injuries to other organs.

A novel approach to assessing cardiotoxic effects of nanoparticles in a toxicological experiment

Introduction. The study of nanoparticles for potential cardiotoxic effects is a comprehensive multi-stage process based on an integrated approach. Along with generally accepted research methods, molecular biology techniques using modern highly sensitive equipment are being actively introduced into toxicology testing. The aim of the study was to describe a novel approach to assessing cardiotoxic effects of nanoparticles, from the molecular level to the functional response of the whole organism. Materials and methods. Our new approach to assessing cardiotoxic effects of nanoparticles in rats included the examination of changes at the molecular (e.g., the ratio of myosin heavy chains), subcellular (by electron microscopy), cellular and tissue (by histological testing), system and organ (by non-invasive recording of electrocardiogram and blood pressure parameters and biochemical testing of blood serum) levels. We have tested the proposed approach by evaluating lead (PBO) and cadmium oxide (CdO) nanoparticles in rats. Results. Hypotension observed after PbO and/or CdO nanoparticle exposure indicates to the damage to the vascular bed due to penetration and accumulation of the nanoparticles in vascular cells, as well as direct damage to the endothelium, increased oxidative stress, and inflammation. In accordance with the system for assessing nanoparticle-induced cardiotoxicity developed on the basis of toxicology test results, lead and cadmium oxides, both separately and combined, have a pronounced cardiotoxic effect. Limitations. Our work was limited to examining the main indicators of the cardiotoxic effects of nanoparticles in a toxicological experiment on one animal species (rats). Conclusion. The data analysis revealed varying degrees of manifestation of nanoparticle cardiotoxicity, both at the molecular level and at the intracellular, cellular, tissue, organ, and body levels. The use of this approach will allow a better in-depth assessing effects of nano-sized particles on the heart and blood vessels for identification of risks for cardiovascular disease.

Assessment of disorders of metabolic process on the base of quantification of target proteins under aerogenic influence of aluminum oxide in children

Introduction. The study of the mechanisms of the occurrence of adverse events at the molecular level, followed by the study of biological processes at the cellular, tissue, and organ level, allows further investigating the mechanism of the toxic action of chemicals to predict the development of adverse effects in humans. The purpose of the study is to evaluate disturbances in the signal-transporter pathways of metabolic processes on the base of the quantification of identified target proteins under aerogenic exposure to aluminum oxide in children. Materials and methods. Using the methods of chemical-analytical, statistical, proteomic, biochemical, histological research, and bioinformation analysis, the adverse effects were assessed in 4–7 years children and Wistar rats exposed to aerogenic and inhalation exposure to aluminum oxide (Al2O3). A comparative analysis of the results obtained in the experiment and natural conditions was carried out. Results. In children under conditions of long-term aerogenic exposure to Al2O3 at the level of 0.1–1.0 RfC, the urine concentration of the studied substance was found to be up to 2 times higher than the average comparison value and the reference value. In the experiment with chronic inhalation of Al2O3 at a dose equivalent to the real one, the aluminum urine content in rats was 3.5 times higher than the control value. Comparative analysis of proteomic maps in children revealed 23 significantly different protein spots, 8 of which had a relationship between intensity changes and an increase in Al urine concentration. In rats, 15 significantly different protein spots were found between the groups, 13 of which had a reliable relationship with the exposure marker. In natural and experimental studies, only two identical proteins were found: apolipoprotein A-I and transthyretin; increased levels of ALAT, ASAT and alkaline phosphatase, total and direct bilirubin, gamma-aminobutyric and glutamic acids, lipid hydroperoxide in the blood serum; increased MDA and decreased AOA in the blood plasma. Pathomorphological changes in the tissues of the brain, heart, and liver were confirmed in the experiment. Limitations. The research conducted allows drawing a conclusion about the effect of Al2O3 on the body only through the aerogenic route of entry. Conclusion. Based on the bioinformational analysis of the results obtained and assessment of the cause-and-effect relationships of the transformation of the proteomic profile of blood plasma under natural conditions, verified in the experiment, the leading molecular-cellular events in the development of adverse effects in the form of oxidation, imbalance of lipoprotein and neurotransmitter metabolism, and decreased neurogenesis activity were identified. Metabolic disorders are predicted in the tissues of the heart, blood vessels, liver, and brain under continued conditions of aerogenic exposure to Al2O3. The study of the cascade of events of adverse responses (from the molecular to the organ level) expands knowledge about the pathogenetic mechanisms of metabolic processes of dysregulation of signal-transporter pathways in the human body in response to the influence of a chemical factor, including Al2O3. This increases the effectiveness of early prediction of the occurrence of the disease and the development of targeted measures to prevent adverse consequences.