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The rat myocardial infarction (MI) model is widely used to study left ventricular (LV) remodeling. In this study, acipimox-enhanced (18)F-Fluorodeoxyglucose (FDG) gated-positron emission tomography (PET) was assessed for characterizing and predicting early remodeling in the rat infarct model. Nineteen Wistar rats had surgical occlusion of the left anterior descending coronary artery and 7 were sham-operated. PET was scheduled 48 h and 2 weeks later for quantifying MI area and LV function. Segments with <50% of FDG uptake had histological evidence of MI (74 ± 9% decrease in parietal thickness, fibrosis development). At 48 h, MI area was large (>35% of LV) in 6 rats, moderate (15-35% of LV) in 8 rats, limited (<15% of LV) in 5 rats and absent in the 7 sham rats. LV remodeling, assessed through the 2 weeks increase in end-diastolic volume, increased between rats with limited, moderate and large MI (+72 ± 25, +109 ± 56, +190 ± 69 μl, respectively, P = 0.007). This 3-groups classification allowed predicting 44% of the 2 weeks increase in end-diastolic volume, and additional 34% were predicted by heart rate at 48 h. The acipimox-enhanced FDG gated-PET technique provides efficient characterization and prediction of early remodeling in the rat infarct model. [ABSTRACT FROM AUTHOR]

Context: The mechanisms of Traditional Chinese Medicine (TCM) Guizhi-Gancao Decoction (GGD) remain unknown. Objective: This study explores the mechanisms of GGD against cardiac hypertrophy. Materials and methods: Network pharmacology analysis was carried out to identify the potential targets of GGD. In vivo experiments, C57BL/6J mice were divided into Con, phenylephrine (PE, 10 mg/kg/d), 2-chloroadenosine (CADO, the stable analogue of adenosine, 2 mg/kg/d), GGD (5.4 g/kg/d) and GGD (5.4 g/kg/d) + CGS15943 (a nonselective adenosine receptor antagonist, 4 mg/kg/d). In vitro experiments, primary neonatal rat cardiomyocytes (NRCM) were divided into Con, PE (100 µM), CADO (5 µM), GGD (10−5 g/mL) and GGD (10−5 g/mL) + CGS15943 (5 µM). Ultrasound, H&E and Masson staining, hypertrophic genes expression and cell surface area were conducted to verify the GGD efficacy. Adenosine receptors (ADORs) expression were tested via real-time polymerase chain reaction (PCR), western blotting and immunofluorescence analysis. Results: Network pharmacology identified ADORs among those of the core targets of GGD. In vitro experiments demonstrated that GGD attenuated PE-induced increased surface area (with an EC50 of 5.484 × 10−6 g/mL). In vivo data shown that GGD attenuated PE-induced ventricular wall thickening. In vitro and in vivo data indicated that GGD alleviated PE-induced hypertrophic gene expression (e.g., ANP, BNP and MYH7/MYH6), A1AR over-expression and A2aAR down-expression. Moreover, CADO exerts effects similar to GGD, whereas CGS15943 eliminated most effects of GGD. Discussion and conclusions: Our findings suggest the mechanism by which GGD inhibits cardiac hypertrophy, highlighting regulation of ADORs as a potential therapeutic strategy for HF. [ABSTRACT FROM AUTHOR]

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four 18F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib. All four probes were characterized by cellular uptake studies with U87 glioma cells harboring a heterozygous IDH1 mutation (U87-mIDH) and the corresponding wildtype cells (U87-WT). In addition, the most promising probe was evaluated by PET imaging in healthy mice and mice bearing subcutaneous U87-mIDH and U87-WT tumors. Although all four probes inhibited mIDH1 with variable potencies, only one of them ([18F]mIDH-138) showed significantly higher in vitro uptake into U87-mIDH compared to U87-WT cells. In addition, PET imaging with [18F]mIDH-138 in mice demonstrated good in vivo stability and low non-specific uptake of the probe, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH tumors. Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) pose a significant burden on global health. Developing effective diagnostic, therapeutic, and prognostic indicators for CVDs is critical. This narrative review explores the role of select non-coding RNAs (ncRNAs) and provides an in-depth exploration of the roles of miRNAs, lncRNAs, and circRNAs in different aspects of CVDs, offering insights into their mechanisms and potential clinical implications. The review also sheds light on the diverse functions of ncRNAs, including their modulation of gene expression, epigenetic modifications, and signaling pathways. It comprehensively analyzes the interplay between ncRNAs and cardiovascular health, paving the way for potential novel interventions. Finally, the review provides insights into the methodologies used to investigate ncRNA-mediated gene regulation in CVDs, as well as the implications and challenges associated with translating ncRNA research into clinical applications. Considering the broader implications, this research opens avenues for interdisciplinary collaborations, enhancing our understanding of CVDs across scientific disciplines. [ABSTRACT FROM AUTHOR]

The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts. [ABSTRACT FROM AUTHOR]

Simple Summary: We review recent advances in imaging techniques and applications of artificial intelligence to improve the diagnosis and prognosis of high-grade gliomas, the deadliest brain tumors. Although these technological advances promise to improve the precision of radiotherapy and optimize treatment, they have yet to translate into widespread clinical benefits for patients with high-grade glioma. We discuss possible measures to accelerate technology transfer from bench to bedside. High-grade gliomas, to date, remain essentially fatal tumors, and the often unmet need to adapt legislative instruments to the end of life of patients is also discussed. The first half of 2022 saw the publication of several major research advances in image-based models and artificial intelligence applications to optimize treatment strategies for high-grade gliomas, the deadliest brain tumors. We review them and discuss the barriers that delay their entry into clinical practice; particularly, the small sample size and the heterogeneity of the study designs and methodologies used. We will also write about the poor and late palliation that patients suffering from high-grade glioma can count on at the end of life, as well as the current legislative instruments, with particular reference to Italy. We suggest measures to accelerate the gradual progress in image-based models and end of life care for patients with high-grade glioma. [ABSTRACT FROM AUTHOR]

Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[11C]methionine and [11C]choline, was performed, using a microfluidic cassette and an iMiDEVTM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[11C]methionine and [11C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [11C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[11C]methionine and >60% for [11C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[11C]methionine and [11C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields. [ABSTRACT FROM AUTHOR]

Background: The demand for 68Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, 68Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([68Ga]Ga-FAPI-46) in late-phase studies, whereas [68Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach. Results: Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [68Ga]Ga-FAPI-46 and 46 ± 7% for [68Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including 68Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers. Conclusions: The microfluidic-based approach enabled the implementation of radiosynthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2–3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [68Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future. [ABSTRACT FROM AUTHOR]

Purpose: Long non-coding RNAs (lncRNAs) constitute a novel class of non-coding RNAs. LncRNAs regulate gene expression, thus having the possibility to modulate disease progression. In this study, we investigated the expression of lncRNAs in the heart after myocardial infarction (MI).Methods: Adult male C57/BL6 mice were subjected to coronary ligation or sham operation. Cardiac gene expression was investigated using whole-genome microarrays with an in-house analytical pipeline dedicated to lncRNAs. Cardiac function was evaluated by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET).Results: In a derivation group of 4 MI and 4 sham-operated mice sacrificed 24 hours after surgery, microarray analysis showed that MI significantly affected the cardiac transcriptome. 20 lncRNAs were up-regulated in the MI group, and 10 lncRNAs were down-regulated in the MI group (fold-change >2, false discovery rate <5%). Among these, 2 lncRNAs (called lncRNA1 and lncRNA2) showed robust up-regulation in the MI group: lncRNA1 (5-fold) and lncRNA2 (13-fold). This was confirmed using quantitative PCR, in which lncRNA1 and lncRNA2 displayed 6- and 12-fold up-regulation in the MI group, respectively (both P<0.05). Up-regulation of these 2 lncRNAs after MI was further confirmed in an independent validation group of 8 MI and 8 sham-operated mice (9-fold and 16-fold for lncRNA1 and lncRNA2, P<0.001). In a time-course analysis involving 21 additional MI mice, the expression of both lncRNAs peaked 24 hours after induction of MI and returned to basal levels after 2 days. In situ hybridization revealed an increase of lncRNA1 expression in the left ventricle of MI mice. Both lncRNAs were robustly correlated with left ventricular ejection fraction determined 24 hours after MI by 18F-FDG PET (r>0.8). Bioinformatic analyses of microarray data revealed that lncRNA1 expression displayed strong association with genes coding for proteins involved in angiogenesis, fibrosis, hypertrophy, inflammation, and extracellular matrix remodeling, all pathways involved in the development of left ventricular remodeling and heart failure post MI. Among the genes most highly correlated with lncRNA1 (r>0.80), MMP9, TNFalpha, CXCR4, and BNP were all up-regulated in the heart of MI mice.Conclusion: We show for the first time that expression of lncRNAs is regulated in the infarcted heart. This study provides the basis for future investigations of the role of lncRNAs in the diseased heart. [ABSTRACT FROM PUBLISHER]

Long non-coding RNAs (lncRNAs) are non-coding RNA molecules longer than 200 nucleotides that regulate gene expression at the transcriptional, post-transcriptional, and translational levels. Abnormal expression of lncRNAs has been identified in many human diseases. Future improvements in diagnostic, prognostic, and therapeutic techniques will be facilitated by a deeper understanding of disease etiology. Cardiovascular diseases (CVDs) are the main cause of death globally. Cardiac development involves lncRNAs, and their abnormalities are linked to many CVDs. This review examines the relationship and function of lncRNA in a variety of CVDs, including atherosclerosis, myocardial infarction, myocardial hypertrophy, and heart failure. Therein, the potential utilization of lncRNAs in clinical diagnostic, prognostic, and therapeutic applications will also be discussed. [ABSTRACT FROM AUTHOR]

Introduction: L’implantation intramyocardique des cellules souches mésenchymateuses (CSMs) améliore la reperfusion de l’infarctus myocardique chronique (IMc). Cependant, l’effet thérapeutique à long terme, après des phénomènes inflammatoires consécutifs aux injections cellulaires, n’est pas élucidé. Cette étude préclinique randomisée avait pour but d’évaluer les variations temporelles des segments IMc traités avec des CSMs. Méthodes: 14 rats (IDMc>4 mois) étaient répartis entre le groupe contrôle (injection de liquide physiologique, n=7) ou le groupe traité recevant une injection de 2x106 CSM préalablement marquées à 111In-oxine (n=7). L’évaluation de la distribution des greffons CSMs se faisait grâce aux examens SPECT 111In/99mTc à 48 Heures et la perfusion par un monitorage séquentiel au Sestamibi pinhole gated-SPECT (avant et pendant 6 mois après traitement). Résultats: L’examen post-thérapeutique à 48 H a montré une majoration significative de la reperfusion myocardique du groupe contrôle (+ 8 ±5 % en terme de % d’augmentation de la captation de Sestamibi) et du groupe thérapie (zone traitée=+13±15 % et zones avoisinantes +7±7 %). Cette augmentation était persistante durant les 6 mois de suivi dans les segments avoisinants de greffe cellulaire (+10±5 %) alors qu’elle déclinait progressivement aussi bien dans les zones traitées (groupe thérapie=-9±10 %) que dans celles recevant le liquide physiologique (groupe contrôle=-5±3 %). Conclusions: L’augmentation de la perfusion myocardique de zones IMc suite à l’implantation de CSMs est (i) précoce et probablement associée à de réactions inflammatoires non-spécifiques et (ii) soutenue à long terme surtout dans les zones éloignées des sites d’implantations suggérant un effet paracrine des CSMs. [Copyright &y& Elsevier]

Introduction: Les études sur l’hypertension artérielle sont souvent réalisées sur des rats qui sont issus de la race Wistar Kyoto (WKY) et qui présentent une hypertension artérielle isolée (SHR) ou associée à un syndrome métabolique (SHHF). Cette hypertension est susceptible d’entraîner une insuffisance cardiaque et des accidents cérébraux dont les mécanismes initiaux sont mal connus. Cette étude avait pour but de rechercher ces mécanismes avec un appareil de microTEP à haute résolution permettant d’explorer conjointement : le fonctionnement cardiaque, les résistances périphériques vasculaires et les zones d’hyper ou d’hypoactivité cérébrale. Matériels et Méthodes: 74 MBq de 18F-Fluorodésoxyglucose (FDG) ont été injectés par voie intraveineuse chez des jeunes rats de 3 mois : 5 WKY, 5 SHR et 5 SHHF. Trente minutes plus tard, l’activité cérébrale était enregistrée pendant une durée de 30 min, puis l’activité cardiaque était enregistrée sur 20min. Résultats: Les résistances vasculaires périphériques totales étaient plus élevées dans les 2 groupes de rats hypertendus (mmHg. min.ml-1, SHR : 2,4±0,4, SHHF : 2,6±0,4s. WKY : 1,3±0,6, P<0,05) expliquant une augmentation significative de la rigidité artérielle mesurée par la vitesse de l’onde pouls. Les volumes et fractions d’éjection du ventricule gauche étaient identiques dans les 3 groupes, mais les pics de remplissage diastolique plus faibles chez les rats hypertendus (en ml.s-1, SHR : 4,4±0,1, SHHF : 4,5±0,7vs. WKY : 5,2±0,7, P<0,05). Enfin, des zones d’hypoactivité cérébrale ont été observées chez les rats SHR et SHHF. Celles-ci étaient identiques et localisées sur le tronc cérébral, dans la région du noyau du tractus solitaire qui régule les variations du tonus sympathique. Conclusion: à l’âge de 3 mois, les rats SHR et SHHF présentent : (i) des résistances périphériques déjà très élevées, (ii) peu de retentissement cardiaque mais (iii) un remodelage cérébral marqué avec des variations de l’activité de centres régulant le tonus sympathique. [Copyright &y& Elsevier]

Contexte: L’homocystéine est un facteur de risque des maladies cardiovasculaires. Les perturbations des activités du cycle de reméthylation de l’homocystéine, liées à une carence de groupements méthyles, seraient probablement impliquées dans la pathogénèse de ces maladies. Objectif: Etudier les répercutions du régime carencé en donneurs de méthyles sur le myocarde des ratons nés de mères carencées, et déterminer les effets sur les activités enzymatiques du cycle de l’homocystéine, et sur le métabolisme lipidique. Méthodes: Modèle : Rats Wistar alimentés avec un régime carencé un mois avant la mise en accouplement et poursuivi jusqu’au sevrage. Analyses Biochimiques : Dosages vitaminiques, activités enzymatiques, métabolites du cycle de l’homocystéine, concentration en carnitine, BNP et récepteurs d’adénosine. Voies de signalisation. Protéines AKT/PKB (hypertrophie) Analyses Fonctionnelles. Fraction d’éjection (FEVG) par miniPET et mesure de la pression artérielle. Résultats: La carence maternelle diminue les concentrations plasmatiques en vitamines B9 et B12 et une hyperhomocystéinémie. On observe une augmentation des taux de SAM et de SAH ainsi que de l’activité MS. Histologie : Hypertrophie myocardique. Augmentation significative du taux de BNP plasmatique en absence d’une dysfonction systolique chez le rat carencé. Parallèlement il y a une augmentation du récepteur A2A. Il existe un effet ambivalent de l’hyperhomocystéinemie sur les acylcarnitines avec une augmentation au niveau plasmatique et une diminution au niveau tissulaire chez le rat carencé. La carence n’induit pas de modification de l’expression des certaines protéines impliquées dans le voies AKT/PKB. Conclusion: Chez le raton carencé les modifications du BNP témoignent d’un stress de la paroi myocardique. Puisque les acides gras sont la principale source d’énergie du myocarde, un déficit en acylcarnitine suggère un problème de production d’énergie qui pourrait expliquer l’hypertrophie par un mécanisme adaptatif. [Copyright &y& Elsevier]

Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target. However, current clinical methods for detecting mutated IDH (mIDH) require invasive tissue sampling and cannot be used for follow-up examinations or longitudinal studies. PET imaging could be a promising approach for non-invasive assessment of the IDH status in gliomas, owing to the availability of various mIDH-selective inhibitors as potential leads for the development of PET tracers. In the present review, we summarize the rationale for the development of mIDH-selective PET probes, describe their potential applications beyond the assessment of the IDH status and highlight potential challenges that may complicate tracer development. In addition, we compile the major chemical classes of mIDH-selective inhibitors that have been described to date and briefly consider possible strategies for radiolabeling of the most promising candidates. Where available, we also summarize previous studies with radiolabeled analogs of mIDH inhibitors and assess their suitability for PET imaging in gliomas. [ABSTRACT FROM AUTHOR]

Both microRNAs (miRNAs) and purinergic signalling are widely and respectively expressed in various tissues of different organisms and play vital roles in a variety of physiological and pathological processes. Here, we reviewed the current publications contributed to the relationship of miRNAs and purinergic signalling in cardiovascular diseases, gastrointestinal diseases, neurological diseases, and ophthalmic diseases. We tried to decode the miRNAs-purinergic signalling network of purinergic signalling involved diseases. The evidence indicated that more than 30 miRNAs (miR-22, miR-30, miR-146, miR-150, miR-155, miR-187, etc.) directly or indirectly modulate P1 receptors (A1, A2A, A2B, A3), P2 receptors (P2X1, P2X3, P2X4, P2X7, P2Y2, P2Y6, P2Y12), and ecto-enzymes (CD39, CD73, ADA2); P2X7 and CD73 could be modulated by multiple miRNAs (P2X7: miR-21, miR-22, miR-30, miR-135a, miR-150, miR-186, miR-187, miR-216b; CD73: miR-141, miR-101, miR-193b, miR-340, miR-187, miR-30, miR-422a); miR-187 would be the common miRNA to modulate P2X7 and CD73. [ABSTRACT FROM AUTHOR]

Human diseases have been a critical threat from the beginning of human history. Knowing the origin, course of action and treatment of any disease state is essential. A microscopic approach to the molecular field is a more coherent and accurate way to explore the mechanism, progression, and therapy with the introduction and evolution of technology than a macroscopic approach. Non-coding RNAs (ncRNAs) play increasingly important roles in detecting, developing, and treating all abnormalities related to physiology, pathology, genetics, epigenetics, cancer, and developmental diseases. Noncoding RNAs are becoming increasingly crucial as powerful, multipurpose regulators of all biological processes. Parallel to this, a rising amount of scientific information has revealed links between abnormal noncoding RNA expression and human disorders. Numerous non-coding transcripts with unknown functions have been found in addition to advancements in RNA-sequencing methods. Non-coding linear RNAs come in a variety of forms, including circular RNAs with a continuous closed loop (circRNA), long non-coding RNAs (lncRNA), and microRNAs (miRNA). This comprises specific information on their biogenesis, mode of action, physiological function, and significance concerning disease (such as cancer or cardiovascular diseases and others). This study review focuses on non-coding RNA as specific biomarkers and novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Candida albicans is one of the most commonly found species in fungal infections. Due to its clinical importance, molecular aspects of the host immune defense against the fungus are of interest to biomedical sciences. Long non-coding RNAs (lncRNAs) have been investigated in different pathologies and gained widespread attention regarding their role as gene regulators. However, the biological processes in which most lncRNAs perform their function are still unclear. This study investigates the association between lncRNAs with host response to C. albicans using a public RNA-Seq dataset from lung samples of female C57BL/6J wild-type Mus musculus with induced C. albicans infection. The animals were exposed to the fungus for 24 h before sample collection. We selected lncRNAs and protein-coding genes related to the host immune response by combining the results from different computational approaches used for gene selection: differential expression gene analysis, co-expression genes network analysis, and machine learning-based gene selection. Using a guilt by association strategy, we inferred connections between 41 lncRNAs and 25 biological processes. Our results indicated that nine up-regulated lncRNAs were associated with biological processes derived from the response to wounding: 1200007C13Rik, 4833418N02Rik, Gm12840, Gm15832, Gm20186, Gm38037, Gm45774, Gm4610, Mir22hg, and Mirt1. Additionally, 29 lncRNAs were related to genes involved in immune response, while 22 lncRNAs were associated with processes related to reactive species production. These results support the participation of lncRNAs during C. albicans infection, and may contribute to new studies investigating lncRNA functions in the immune response. [ABSTRACT FROM AUTHOR]

After fluid status optimization, norepinephrine infusion represents the cornerstone of septic shock treatment. De-escalation of vasopressors should be considered with caution, as hypotension increases the risk of mortality. In this prospective observational study including 42 patients, we assess the role of dynamic elastance (EaDyn), i.e., the ratio between pulse pressure variation and stroke volume variation, which can be measured noninvasively by the MostCare monitoring system, to predict a mean arterial pressure (MAP) drop > 10% 30 min after norepinephrine reduction. Patients were divided into responders (MAP falling > 10%) and non-responders (MAP falling < 10%). The receiver-operating-characteristic curve identified an area under the curve of the EaDyn value to predict a MAP decrease > 10% of 0.84. An EaDyn cut-off of 0.84 predicted a MAP drop > 10% with a sensitivity of 0.71 and a specificity of 0.89. In a multivariate logistic regression, EaDyn was significantly and independently associated with MAP decrease (OR 0.001, 95% confidence interval 0.00001–0.081, p < 0.001). The nomogram model for the probability of MAP decrease > 10% showed a C-index of 0.90. In conclusion, in a septic shock cohort, EaDyn correlates well with the risk of decrease of MAP > 10% after norepinephrine reduction. [ABSTRACT FROM AUTHOR]

In the last decade, microfluidic techniques have been explored in radiochemistry, and some of them have been implemented in preclinical production. However, these are not suitable and reliable for preparing different types of radiotracers or dose-on-demand production. A fully automated iMiDEV™ microfluidic radiosynthesizer has been introduced and this study is aimed at using of the iMiDEV™ radiosynthesizer with a microfluidic cassette to produce [11C]flumazenil and [11C]L-deprenyl. These two are known PET radioligands for benzodiazepine receptors and monoamine oxidase-B (MAO-B), respectively. Methods were successfully developed to produce [11C]flumazenil and [11C]L-deprenyl using [11C]methyl iodide and [11C]methyl triflate, respectively. The final products 1644 ± 504 MBq (n = 7) and 533 ± 20 MBq (n = 3) of [11C]flumazenil and [11C]L-deprenyl were produced with radiochemical purities were over 98% and the molar activity for [11C]flumazenil and [11C]L-deprenyl was 1912 ± 552 GBq/µmol, and 1463 ± 439 GBq/µmol, respectively, at the end of synthesis. All the QC tests complied with the European Pharmacopeia. Different parameters, such as solvents, bases, methylating agents, precursor concentration, and different batches of cassettes, were explored to increase the radiochemical yield. Synthesis methods were developed using 3–5 times less precursor than conventional methods. The fully automated iMiDEV™ microfluidic radiosynthesizer was successfully applied to prepare [11C]flumazenil and [11C]L-deprenyl. [ABSTRACT FROM AUTHOR]

Considering the individual characteristics of positron emission tomography (PET) and optical imaging (OI) in terms of sensitivity, spatial resolution, and tissue penetration, the development of dual imaging agents for bimodal PET/OI imaging is a growing field. A current major breakthrough in this field is the design of monomolecular agent displaying both a radioisotope for PET and a fluorescent dye for OI. We took advantage of the multifunctionalities allowed by a clickable C-glycosyl scaffold to gather the different elements. We describe, for the first time, the synthesis of a cyanine-based dual PET/OI imaging probe based on a versatile synthetic strategy and its direct radiofluorination via [18F]F-C bond formation. The non-radioactive dual imaging probe coupled with two c(RGDfK) peptides was evaluated in vitro and in vivo in fluorescence imaging. The binding on αvβ3 integrin (IC50 = 16 nM) demonstrated the efficiency of the dimeric structure and PEG linkers in maintaining the affinity. In vivo fluorescence imaging of U-87 MG engrafted nude mice showed a high tumor uptake (40- and 100-fold increase for orthotopic and ectopic brain tumors, respectively, compared to healthy brain). In vitro and in vivo evaluations and resection of the ectopic tumor demonstrated the potential of the conjugate in glioblastoma cancer diagnosis and image-guided surgery. [ABSTRACT FROM AUTHOR]

Despite unquestionable progress in interventional and pharmacologic therapies of ischemic heart disease, the number of patients with chronic ischemic heart failure is increasing and the prognosis remains poor. Repair/restoration of functional myocardium through progenitor cell-mediated (PCs) healing and renovation of injured myocardium is one of the pivotal directions in biomedical research. PCs release numerous pro-angiogenic and anti-apoptotic factors. Moreover, they have self-renewal capability and may differentiate into specialized cells that include endothelial cells and cardiomyocytes. Uptake and homing of PCs in the zone(s) of ischaemic injury (i.e., their effective transplantation to the target zone) is an essential pre-requisite for any potential therapeutic effect; thus effective cell tracking is fundamental in pre-clinical and early clinical studies. Another crucial requirement in rigorous research is quantification of the infarct zone, including the amount of non-perfused and hypo-perfused myocardium. Quantitative and reproducible evaluation of global and regional myocardial contractility and left ventricular remodeling is particularly relevant in clinical studies. Using SPECT, our earlier work has addressed several critical questions in cardiac regenerative medicine including optimizing transcoronary cell delivery, determination of the zone(s) of myocardial cell uptake, and late functional improvement in relation to the magnitude of cell uptake. Here, we review the role of single-photon emission computed tomography (SPECT), a technique that offers high-sensitivity, quantitative cell tracking on top of its ability to evaluate myocardial perfusion and function on both cross-sectional and longitudinal bases. SPECT, with its direct relevance to routine clinical practice, is a fundamental tool in evaluation of myocardial reparation and regeneration therapies. [ABSTRACT FROM AUTHOR]

Aerobic physical training reduces arterial pressure in patients with hypertension owing to integrative systemic adaptations. One of the key factors is the decrease in cardiac sympathetic influence. Thus, we hypothesized that among other causes, cardiac sympathetic influence reduction might be associated with intrinsic cardiac adaptations that provide greater efficiency. Therefore, 14 spontaneously hypertensive rats (SHR group) and 14 normotensive Wistar Kyoto rats (WKY group) were used in this study. Half of the rats in each group were trained to swim for 12 weeks. All animals underwent the following experimental protocols: double blockade of cardiac autonomic receptors with atropine and propranolol; echocardiography; and analysis of coronary bed reactivity and left ventricle contractility using the Langendorff technique. The untrained SHR group had a higher sympathetic tone, cardiac hypertrophy, and reduced ejection fraction compared with the untrained WKY group. In addition, reduced coronary bed reactivity due to increased flow, and less ventricular contractile response to dobutamine and salbutamol administration were observed. The trained SHR group showed fewer differences in echocardiographic parameters as the untrained SHR group. However, the trained SHR group showed a reduction in the cardiac sympathetic influence, greater coronary bed reactivity, and increased left intraventricular pressure. In conclusion, aerobic physical training seems to reduce cardiac sympathetic influence and increase contractile strength in SHR rats, besides the minimal effects on cardiac morphology. This reduction suggests intrinsic cardiac adaptations resulting in beneficial adjustments of coronary bed reactivity associated with greater left ventricular contraction. [ABSTRACT FROM AUTHOR]

Simple Summary: Betaine supplementation has ergogenic potential for exercise performance, but the effect of betaine supplementation in combination with training for 6 weeks is still unclear. The present study aimed to investigate the effects of betaine supplementation on muscular power and maximal strength in collegiate male athletes. The participants in the study received either 5 g/day of betaine or placebo for 6 weeks, during which they maintained their regular exercise training. The overhead medicine-ball throw, countermovement jump, and one repetition-maximum of a bench press, overhead press, half squat, and sumo dead lift by the participants were assessed before and after betaine supplementation. Blood lipids were also analyzed before and after betaine supplementation. We found that receiving 5 g of betaine supplementation daily during the 6-week preparatory period had extra benefits on the power of the upper body and maximal strength on the half squat and overhead press. Betaine seems to be a useful nutritional strategy to improve and maintain performance during 6-week preparatory periods in collegiate athletes. The purpose of this study was to investigate the effects of 6-week betaine supplementation during a preparatory period of collegiate athletes on muscular power and strength. Sixteen male collegiate athletes received 5 g/day of betaine (betaine group, n = 9) or carboxymethyl cellulose (placebo group, n = 7) for 6 weeks. All participants engaged in their regular training during the experimental period. The overhead medicine-ball throw (OMBT), countermovement jump, and maximal strength (one repetition maximum, 1-RM) on the bench press, overhead press, half squat, and sumo dead lift by the participants were assessed before and after betaine supplementation. Blood lipids were also analyzed before and after betaine supplementation. After supplementation, there were no significant differences between betaine and placebo groups on any variables. Compared to presupplementation, the performance of OMBT and 1-RM of overhead press and half squat in the betaine group had significantly improved (p < 0.05). By contrast, no significant differences were observed in the placebo group before and after supplementation. Blood analysis revealed no negative effect on blood lipid profiles. Betaine seems to be a useful nutritional strategy to improve and maintain performance during 6-week preparatory periods in collegiate athletes. [ABSTRACT FROM AUTHOR]

Although the tracer (2S,4S)4–[18F]FPArg is expected to provide a powerful imaging method for the diagnosis and treatment of clinical tumors, it has not been realized due to the low yield of chemical synthesis and radiolabeling. A simple synthetic method for the radiolabeled precursor of (2S,4S)4–[18F]FPArg in stable yield was obtained by adjusting the sequence of the synthetic steps. Furthermore, the biodistribution experiments confirmed that (2S,4S)4–[18F]FPArg could be cleared out quickly in wild type mouse. Cell uptake experiments and U87MG tumor mouse microPET–CT imaging experiments showed that the tumor had high uptake of (2S,4S)4–[18F]FPArg and the clearance was slow, but (2S,4S)4–[18F]FPArg was rapidly cleared in normal brain tissue. MicroPET–CT imaging of nude mice bearing orthotopic HS683–Luc showed that (2S,4S)4–[18F]FPArg can penetrate blood–brain barrier and image gliomas with a high contrast. Therefore, (2S,4S)4–[18F]FPArg is expected to be further applied in the diagnosis and efficacy evaluation of clinical glioma. [ABSTRACT FROM AUTHOR]

Vitamin B12 (VB12) is a micronutrient that is essential for DNA synthesis and cellular energy production. We recently demonstrated that VB12 oral supplementation coordinates ileal epithelial cells (iECs) and gut microbiota functions to resist pathogen colonization in mice, but it remains unclear whether VB12 directly modulates the cellular homeostasis of iECs derived from humans. Here, we integrated transcriptomic, metabolomic, and epigenomic analyses to identify VB12-dependent molecular and metabolic pathways in human iEC microtissue cultures. RNA sequencing (RNA-seq) revealed that VB12 notably activated genes involved in fatty acid metabolism and epithelial cell proliferation while suppressing inflammatory responses in human iECs. Untargeted metabolite profiling demonstrated that VB12 facilitated the biosynthesis of amino acids and methyl groups, particularly S-adenosylmethionine (SAM), and supported the function of the mitochondrial carnitine shuttle and TCA cycle. Further, genome-wide DNA methylation analysis illuminated a critical role of VB12 in sustaining cellular methylation programs, leading to differential CpG methylation of genes associated with intestinal barrier function and cell proliferation. Together, these findings suggest an essential involvement of VB12 in directing the fatty acid and mitochondrial metabolisms and reconfiguring the epigenome of human iECs to potentially support cellular oxygen utilization and cell proliferation. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic joint disorder that causes cartilage degradation and subchondral bone abnormalities. Nangibotide, also known as LR12, is a dodecapeptide with considerable anti-inflammatory properties, but its significance in OA is uncertain. The aim of the study was to determine whether nangibotide could attenuate the progression of OA, and elucidate the underlying mechanism. In vitro experiments showed that nangibotide strongly inhibited TNF-α-induced osteogenic reduction, significantly enhanced osteoblast proliferation and prevented apoptosis in MC3T3-E1 cells. Male C57BL/6 J mice aged 2 months were randomly allocated to three groups: sham, ACLT, and ACLT with nangibotide therapy. Nangibotide suppressed ACLT-induced cartilage degradation and MMP-13 expression. MicroCT analysis revealed that nangibotide attenuated in vivo subchondral bone loss induced by ACLT. Histomorphometry results showed that nangibotide attenuated ACLT-induced osteoblast inhibition; TUNEL assays and immunohistochemical staining of cleaved-caspase3 further confirmed the in vivo anti-apoptotic effect of nangibotide on osteoblasts. Furthermore, we found that nangibotide exerted protective effects by suppressing TGF-β signaling mediated by Smad2/3 to restore coupled bone remodeling in the subchondral bone. In conclusion, the findings suggest that nangibotide might exert a protective effect on the bone-cartilage unit and maybe an alternative treatment option for OA. [ABSTRACT FROM AUTHOR]

Heart failure is among the most progressive diseases and a leading cause of morbidity. Despite several advances in cardiovascular therapies, pharmacological treatments are limited to relieve symptoms without curing cardiac injury. Multiple observations point to the involvement of immune cells as key drivers in the pathophysiology of heart failure. In particular, there is a growing recognition that heart failure is related to a prolonged and insufficiently repressed inflammatory response leading to molecular, cellular, and functional cardiac alterations. Over the last decades, non-coding RNAs are recognized as prominent mediators of cardiac inflammation, affecting the function of several immune cells. In the current review, we explore the contribution of the diverse immune cells in the progression of heart failure, revealing mechanistic functions for non-coding RNAs in cardiac immune cells as a new and exciting field of investigation. [ABSTRACT FROM AUTHOR]

Aims: Optimal outcome after cardiogenic shock (CS) depends on a coordinated healing response in which both debris removal and extracellular matrix tissue repair play a crucial role. Excessive inflammation can perpetuate a vicious circle, positioning leucocytes as central protagonists and potential therapeutic targets. High levels of circulating Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), were associated with death in acute myocardial infarction confirming excessive inflammation as determinant of bad outcome. The present study aims to describe the association of soluble TREM-1 with 90-day mortality and with various organ injuries in patients with CS. Methods and results: This is a post-hoc study of CardShock, a prospective, multicenter study assessing the clinical presentation and management in patients with CS. At the time of this study, 87 patients had available plasma samples at either baseline, and/or 48 h and/or 96–120 h for soluble TREM-1 (sTREM-1) measurements. Plasma concentration of sTREM-1 was higher in 90-day non-survivors than survivors at baseline [median: 1392 IQR: (724–2128) vs. 621 (525–1233) pg/mL, p = 0.008), 48 h (p = 0.019) and 96–120 h (p = 0.029). The highest tertile of sTREM-1 at baseline (threshold: 1347 pg/mL) was associated with 90-day mortality with an unadjusted HR 3.08 CI 95% (1.48–6.42). sTREM-1 at baseline was not associated to hemodynamic parameters (heart rate, blood pressure, use of vasopressors or inotropes) but rather with organ injury markers: renal (estimated glomerular filtration rate, p = 0.0002), endothelial (bio-adrenomedullin, p = 0.018), myocardial (Suppression of Tumourigenicity 2, p = 0.002) or hepatic (bilirubin, p = 0.008). Conclusion: In CS patients TREM-1 pathway is highly activated and gives an early prediction of vital organ injuries and outcome. [ABSTRACT FROM AUTHOR]

Sepsis is caused by bacterial infections or viral infections. Clinically, there exist confirmed or highly suspected infection foci. Mortality caused by septic shock remains in a high rate even though antibiotic treatment works effectively. In this study, we treat THP-1 cells with 1 ug/mL LPS (lipopolysaccharide) and add paeoniflorin or LR-12 inhibitor. TREM-1 (triggering receptor expressed on myeloid cells-1), IL-6, IL-1β, and TNF-α (tumour necrosis factor alpha (a)-cachectin) were detected by ELISA and qRT-PCR, and western blotting is performed to detect related proteins in the NF-κB signaling pathway. As a result, paeoniflorin can significantly reduce the production of LPS-stimulated TREM-1 as well as inflammatory factors and attenuate the phosphorylation of NF-κB signaling pathway-related factors, such as p65 and IκBα. At the same time, the combined effect of paeoniflorin and LR-12 is more significant. The results of this study solidly prove that paeoniflorin plays a role in inhibiting TREM-1-mediated inflammation and the NF-κB pathway could be a potential mechanism of action. [ABSTRACT FROM AUTHOR]

Nanoparticle toxicity assessments have moved closer to physiological conditions while trying to avoid the use of animal models. An example of new in vitro exposure techniques developed is the exposure of cultured cells at the air–liquid interface (ALI), particularly in the case of respiratory airways. While the commercially available VITROCELL® Cloud System has been applied for the delivery of aerosolized substances to adherent cells under ALI conditions, it has not yet been tested on lung surfactant and semi-adherent cells such as alveolar macrophages, which are playing a pivotal role in the nanoparticle-induced immune response. Objectives: In this work, we developed a comprehensive methodology for coating semi-adherent lung cells cultured at the ALI with aerosolized surfactant and subsequent dose-controlled exposure to nanoparticles (NPs). This protocol is optimized for subsequent transcriptomic studies. Methods: Semi-adherent rat alveolar macrophages NR8383 were grown at the ALI and coated with lung surfactant through nebulization using the VITROCELL® Cloud 6 System before being exposed to TiO 2 NM105 NPs. After NP exposures, RNA was extracted and its quantity and quality were measured. Results: The VITROCELL® Cloud system allowed for uniform and ultrathin coating of cells with aerosolized surfactant mimicking physiological conditions in the lung. While nebulization of 57 μ L of 30 mg/mL TiO 2 and 114 μ L of 15 mg/mL TiO 2 nanoparticles yielded identical cell delivered dose, the reproducibility of dose as well as the quality of RNA extracted were better for 114 μ L. [ABSTRACT FROM AUTHOR]

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk. Creating a surrogate for cardiovascular risk: Clinical trials can be limited by the lack of surrogates for cardiovascular risk, leading to increased costs and potentially delaying important results. Here, Williams et al. used proteomics and machine learning to derive a 27-protein model that could predict the 4-year likelihood of myocardial infarction, heart failure, stroke, or death better than a clinical model. The proteins included in the model represented 10 mechanistic pathways, and 12 were associated with causal genetic traits. This model was validated across more than 11,000 participants from multiple large studies and was sensitive to both adverse and beneficial changes in outcome, suggesting that it has potential as a surrogate end point for use in phase 2 trials. [ABSTRACT FROM AUTHOR]

Methyl-Cobalamin (Cbl) derives from dietary vitamin B12 and acts as a cofactor of methionine synthase (MS) in mammals. MS encoded by MTR catalyzes the remethylation of homocysteine to generate methionine and tetrahydrofolate, which fuel methionine and cytoplasmic folate cycles, respectively. Methionine is the precursor of S-adenosyl methionine (SAM), the universal methyl donor of transmethylation reactions. Impaired MS activity results from inadequate dietary intake or malabsorption of B12 and inborn errors of Cbl metabolism (IECM). The mechanisms at the origin of the high variability of clinical presentation of impaired MS activity are classically considered as the consequence of the disruption of the folate cycle and related synthesis of purines and pyrimidines and the decreased synthesis of endogenous methionine and SAM. For one decade, data on cellular and animal models of B12 deficiency and IECM have highlighted other key pathomechanisms, including altered interactome of MS with methionine synthase reductase, MMACHC, and MMADHC, endoplasmic reticulum stress, altered cell signaling, and genomic/epigenomic dysregulations. Decreased MS activity increases catalytic protein phosphatase 2A (PP2A) and produces imbalanced phosphorylation/methylation of nucleocytoplasmic RNA binding proteins, including ELAVL1/HuR protein, with subsequent nuclear sequestration of mRNAs and dramatic alteration of gene expression, including SIRT1. Decreased SAM and SIRT1 activity induce ER stress through impaired SIRT1-deacetylation of HSF1 and hypomethylation/hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), which deactivate nuclear receptors and lead to impaired energy metabolism and neuroplasticity. The reversibility of these pathomechanisms by SIRT1 agonists opens promising perspectives in the treatment of IECM outcomes resistant to conventional supplementation therapies. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) was primarily identified as a novel disease causing acute respiratory syndrome. However, as the pandemic progressed various cases of secondary organ infection and damage by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, including a breakdown of the vascular barrier. As SARS-CoV-2 gains access to blood circulation through the lungs, the virus is first encountered by the layer of endothelial cells and immune cells that participate in host defense. Here, we developed an approach to study SARS-CoV-2 infection using vasculature-on-a-chip. We first modeled the interaction of virus alone with the endothelialized vasculature-on-a-chip, followed by the studies of the interaction of the virus exposed-endothelial cells with peripheral blood mononuclear cells (PBMCs). In an endothelial model grown on a permeable microfluidic bioscaffold under flow conditions, both human coronavirus (HCoV)-NL63 and SARS-CoV-2 presence diminished endothelial barrier function by disrupting VE-cadherin junctions and elevating the level of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and angiopoietin-2. Inflammatory cytokine markers were markedly more elevated upon SARS-CoV-2 infection compared to HCoV-NL63 infection. Introduction of PBMCs with monocytes into the vasculature-on-a-chip upon SARS-CoV-2 infection further exacerbated cytokine-induced endothelial dysfunction, demonstrating the compounding effects of inter-cellular crosstalk between endothelial cells and monocytes in facilitating the hyperinflammatory state. Considering the harmful effects of SARS-CoV-2 on endothelial cells, even without active virus proliferation inside the cells, a potential therapeutic approach is critical. We identified angiopoietin-1 derived peptide, QHREDGS, as a potential therapeutic capable of profoundly attenuating the inflammatory state of the cells consistent with the levels in non-infected controls, thereby improving the barrier function and endothelial cell survival against SARS-CoV-2 infection in the presence of PBMC. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) is the main feature of obstructive sleep apnea (OSA) and is known to exaggerate cardiac remodeling after myocardial infarction (MI). However, the specific contribution of CIH to overall OSA-induced pathological complications and the transcriptomic mechanisms underlying CIH-exaggerated post-MI remodeling remains unclear. In this study, we used RNA-sequencing to construct the expression profiles of cardiac mRNAs, microRNAs, and long non-coding RNAs (lncRNA) in four groups of C57BL/6J mice (Sham, CIH, MI, MI + CIH) to evaluate how CIH regulates cardiac remodeling after MI. Compared with the other three groups, the MI + CIH group exhibited 345 lncRNAs, 35 microRNAs, and 5,220 differentially expressed mRNAs. Further analysis showed that CIH led to significant changes in Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the differentially expressed mRNAs. Co-expression network analysis identified two core lncRNAs (Mirt1 and AC125351.1) and two core microRNAs (miR-466i-5p and miR-574-5p) during the development of CIH-exaggerated post-MI remodeling, and they were verified by quantitative real-time PCR (qRT-PCR). LncRNA-mRNA correlation analysis further showed that lncRNA Mirt1 was positively correlated with Apbb1ip and Lcp2. In addition, microRNA-mRNA correlation analysis showed that microRNA miR-466i-5p was positively correlated with Snai2, Cdc27, and Ngfr. Furthermore, combining with lncRNA-mRNA and miRNA-mRNA networks, 44 RNAs were identified in the competitive endogenous RNA (ceRNA) network. Mirt1 acts as a ceRNA to bind to miR-466i-5p to further regulate the expression levels of the target gene, thereby aggravating cardiac remodeling after MI. In conclusion, our study provides a systematic perspective on the potential functions of mRNAs, microRNAs, and lncRNAs in CIH-exaggerated post-MI cardiac remodeling. Our data suggest that lncRNA Mirt1 may be the most critical regulator of MI aggravated by CIH. [ABSTRACT FROM AUTHOR]

Background/Aims: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Methods: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. Results: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. Conclusion: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females. [ABSTRACT FROM AUTHOR]

Communication between cells is a foundational concept for understanding the physiology and pathology of biological systems. Paracrine/autocrine signaling, direct cell-to-cell interplay, and extracellular matrix interactions are three types of cell communication that regulate responses to different stimuli. In the heart, cardiomyocytes, fibroblasts, and endothelial cells interact to form the cardiac tissue. Under pathological conditions, such as myocardial infarction, humoral factors released by these cells may induce tissue damage or protection, depending on the type and concentration of molecules secreted. Cardiac remodeling is also mediated by the factors secreted by cardiomyocytes and fibroblasts that are involved in the extensive reciprocal interactions between these cells. Identifying the molecules and cellular signal pathways implicated in these processes will be crucial for creating effective tissue-preserving treatments during or after reperfusion. Numerous therapies to protect cardiac tissue from reperfusion-induced injury have been explored, and ample pre-clinical research has attempted to identify drugs or techniques to mitigate cardiac damage. However, despite great success in animal models, it has not been possible to completely translate these cardioprotective effects to human applications. This review provides a current summary of the principal molecules, pathways, and mechanisms underlying cardiomyocyte and cardiac fibroblast crosstalk during ischemia/reperfusion injury. We also discuss pre-clinical molecules proposed as treatments for myocardial infarction and provide a clinical perspective on these potential therapeutic agents. [ABSTRACT FROM AUTHOR]