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Aims: The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI., Methods and Results: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown., Conclusion: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α-induced mitochondrial injury in experimental diabetes., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Metabolic imbalances and persistent hyperglycemia are widely recognized as driving forces for augmented cytosolic and mitochondrial reactive oxygen species (ROS) in diabetes mellitus (DM), fostering the development of vascular complications such as diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, and diabetic retinopathy. Therefore, specific therapeutic approaches capable of modulating oxidative milieu may provide a preventative and/or therapeutic benefit against the development of cardiovascular complications in diabetes patients. Recent studies have demonstrated epigenetic alterations in circulating and tissue-specific long non-coding RNA (lncRNA) signatures in vascular complications of DM regulating mitochondrial function under oxidative stress. Intriguingly, over the past decade mitochondria-targeted antioxidants (MTAs) have emerged as a promising therapeutic option for managing oxidative stress-induced diseases. Here, we review the present status of lncRNA as a diagnostic biomarker and potential regulator of oxidative stress in vascular complications of DM. We also discuss the recent advances in using MTAs in different animal models and clinical trials. We summarize the prospects and challenges for the use of MTAs in treating vascular diseases and their application in translation medicine, which may be beneficial in MTA drug design development, and their application in translational medicine.

Advances in the field of regenerative medicine and tissue engineering over the past few decades have paved the path for cell-free therapy. Numerous stem cell types, including mesenchymal stem cells (MSCs), have been reported to impart therapeutic effects via paracrine secretion of exosomes. The underlying factors and the associated mechanisms contributing to these MSC-derived exosomes' protective effects are, however, poorly understood, limiting their application in the clinic. The exosomes exhibit a diversified repertoire of functional non-coding RNAs (ncRNAs) and have the potential to transfer these biologically active transcripts to the recipient cells, where they are found to modulate a diverse array of functions. Altered expression of the ncRNAs in the exosomes has been linked with the regenerative potential and development of various diseases, including cardiac, neurological, skeletal, and cancer. Also, modulating the expression of ncRNAs in these exosomes has been found to improve their therapeutic impact. Moreover, many of these ncRNAs are expressed explicitly in the MSC-derived exosomes, making them ideal candidates for regenerative medicine, including tissue engineering research. In this review, we detail the recent advances in regenerative medicine and summarize the evidence supporting the altered expression of the ncRNA repertoire specific to MSCs under different degenerative diseases. We also discuss the therapeutic role of these ncRNA for the prevention of these various degenerative diseases and their future in translational medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pant, Juric, Bosnjak and Dhanasekaran.)

Preclinical investigations in animal models have consistently demonstrated neurobiological changes and life-long cognitive deficits following exposure to widely used anesthetics early in life. However, the mechanisms by which these exposures affect brain function remain poorly understood, therefore, limiting the efficacy of current diagnostic and therapeutic options in human studies. The human brain exhibits an abundant expression of long noncoding RNAs (lncRNAs). These biologically active transcripts play critical roles in a diverse array of functions, including epigenetic regulation. Changes in lncRNA expression have been linked with brain development, normal CNS processes, brain injuries, and the development of neurodegenerative diseases, and many lncRNAs are known to have brain-specific expression. Aberrant lncRNA expression has also been implicated in areas of growing importance in anesthesia-related research, including anesthetic-induced developmental neurotoxicity (AIDN), a condition defined by neurological changes occurring in patients repeatedly exposed to anesthesia, and the related condition of perioperative neurocognitive disorder (PND). In this review, we detail recent advances in PND and AIDN research and summarize the evidence supporting roles for lncRNAs in the brain under both normal and pathologic conditions. We also discuss lncRNAs that have been linked with PND and AIDN, and conclude with a discussion of the clinical potential for lncRNAs to serve as diagnostic and therapeutic targets for the prevention of these neurocognitive disorders and the challenges facing the identification and characterization of associated lncRNAs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Purpose of Review: Cardiovascular toxicity is a leading cause of mortality among cancer survivors and has become increasingly prevalent due to improved cancer survival rates. In this review, we synthesize evidence illustrating how common cancer therapeutic agents, such as anthracyclines, human epidermal growth factors receptors (HER2) monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been evaluated in cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) to understand the underlying mechanisms of cardiovascular toxicity. We place this in the context of precision cardio-oncology, an emerging concept for personalizing the prevention and management of cardiovascular toxicities from cancer therapies, accounting for each individual patient's unique factors. We outline steps that will need to be addressed by multidisciplinary teams of cardiologists and oncologists in partnership with regulators to implement future applications of hiPSCs in precision cardio-oncology., Recent Findings: Current prevention of cardiovascular toxicity involves routine screenings and management of modifiable risk factors for cancer patients, as well as the initiation of cardioprotective medications. Despite recent advancements in precision cardio-oncology, knowledge gaps remain and limit our ability to appropriately predict with precision which patients will develop cardiovascular toxicity. Investigations using patient-specific CMs facilitate pharmacological discovery, mechanistic toxicity studies, and the identification of cardioprotective pathways. Studies with hiPSCs demonstrate that patients with comorbidities have more frequent adverse responses, compared to their counterparts without cardiac disease. Further studies utilizing hiPSC modeling should be considered, to evaluate the impact and mitigation of known cardiovascular risk factors, including blood pressure, body mass index (BMI), smoking status, diabetes, and physical activity in their role in cardiovascular toxicity after cancer therapy. Future real-world applications will depend on understanding the current use of hiPSC modeling in order for oncologists and cardiologists together to inform their potential to improve our clinical collaborative practice in cardio-oncology. When applying such in vitro characterization, it is hypothesized that a safety score can be assigned to each individual to determine who has a greater probability of developing cardiovascular toxicity. Using hiPSCs to create personalized models and ultimately evaluate the cardiovascular toxicity of individuals' treatments may one day lead to more patient-specific treatment plans in precision cardio-oncology while reducing cardiovascular disease (CVD) morbidity and mortality.

Metformin is the first-line medication for treatment of type 2 diabetes and has been shown to reduce heart damage and death. However, mechanisms by which metformin protects human heart remain debated. The aim of the study was to evaluate the cardioprotective effect of metformin on cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) and mitochondria isolated from human cardiac tissue. At concentrations ≤2.5 mM, metformin significantly increased oxygen consumption rate (OCR) in the hiPSC-CMs by activating adenosine monophosphate activated protein kinase (AMPK)-dependent signaling and enhancing mitochondrial biogenesis. This effect was abrogated by compound C, an inhibitor of AMPK. At concentrations >5 mM, metformin inhibited the cellular OCR and triggered metabolic reprogramming by enhancing glycolysis and glutaminolysis in the cardiomyocytes. In isolated cardiac mitochondria, metformin did not increase the OCR at any concentrations but inhibited the OCR starting at 1 mM through direct inhibition of electron-transport chain complex I. This was associated with reduction of superoxide production and attenuation of Ca 2+ -induced mitochondrial permeability transition pore (mPTP) opening in the mitochondria. Thus, in human heart, metformin might improve cardioprotection due to its biphasic effect on mitochondria: at low concentrations, it activates mitochondrial biogenesis via AMPK signaling and increases the OCR; at high concentrations, it inhibits the respiration by directly affecting the activity of complex I, reduces oxidative stress and delays mPTP formation. Moreover, metformin at high concentrations causes metabolic reprogramming by enhancing glycolysis and glutaminolysis. These effects can be a beneficial adjunct to patients with impaired endogenous cardioprotective responses., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diabetic cardiomyopathy (DCM) lacks diagnostic biomarkers. Circulating long non-coding RNAs (lncRNAs) can serve as valuable diagnostic biomarkers in cardiovascular disease. To seek potential lncRNAs as a diagnostic biomarker for DCM, we investigated the genome-wide expression profiling of circulating lncRNAs and mRNAs in type 2 diabetic db/db mice with and without DCM and performed bioinformatic analyses of the deregulated lncRNA-mRNA co-expression network. Db/db mice had obesity and hyperglycemia with normal cardiac function at 6 weeks of age (diabetes without DCM) but with an impaired cardiac function at 20 weeks of age (DCM) on an isolated Langendorff apparatus. Compared with the age-matched controls, 152 circulating lncRNAs, 127 mRNAs and 3355 lncRNAs, 2580 mRNAs were deregulated in db/db mice without and with DCM, respectively. The lncRNA-mRNA co-expression network analysis showed that five deregulated lncRNAs, XLOC015617, AK035192, Gm10435, TCR-α chain, and MouselincRNA0135, have the maximum connections with differentially expressed mRNAs. Bioinformatic analysis revealed that these five lncRNAs were highly associated with the development and motion of myofilaments, regulation of inflammatory and immune responses, and apoptosis. This finding was validated by the ultrastructural examination of myocardial samples from the db/db mice with DCM using electron microscopy and changes in the expression of myocardial tumor necrosis factor-α and phosphorylated p38 mitogen-activated protein kinase in db/db mice with DCM. These results indicate that XLOC015617, AK035192, Gm10435, TCR-α chain, and MouselincRNA0135 are crucial circulating lncRNAs in the pathogenesis of DCM. These five circulating lncRNAs may have high potential as a diagnostic biomarker for DCM.

Background: Human induced pluripotent stem cells (hiPSCs) need to be thoroughly characterized to exploit their potential advantages in various aspects of biomedicine. The aim of this study was to compare the efficiency of cardiomyogenesis of two hiPSCs and two human embryonic stem cell (hESC) lines by genetic living cardiomyocyte labeling. We also analyzed the influence of spontaneous beating on cardiac differentiation., Methods: H1 and H9 hESC lines and C2a and C6a hiPSC lines were induced into in vitro directed cardiac differentiation. Cardiomyogenesis was evaluated by the analysis of cell cluster beating, cardiac protein expression by immunocytochemistry, ability of cells to generate calcium transients, and cardiomyocyte quantification by the myosin light chain 2v-enhanced green fluorescent protein gene construct delivered with a lentiviral vector., Results: Differentiation of all cell lines yielded spontaneously beating cell clusters, indicating the presence of functional cardiomyocytes. After the cell dissociation, H1-hESC-derived cardiomyocytes exhibited spontaneous calcium transients, corresponding to autonomous electrical activity and displayed ability to transmit them between the cells. Differentiated hESC and hiPSC cells exhibited striated sarcomeres and expressed cardiac proteins sarcomeric α-actinin and cardiac troponin T. Cardiomyocytes were the most abundant in differentiated H1 hESC line (20% more than in other tested lines). In all stem cell lines, cardiomyocyte enrichment was greater in beating than in non-beating cell clusters, irrespective of cardiomyogenesis efficiency., Conclusion: Although C2a and C6a hiPSC and H9 hESC lines exhibited efficient cardiomyogenesis, H1 hESC line yielded the greatest cardiomyocyte enrichment of all tested lines. Beating of cell clusters promotes cardiomyogenesis in tested hESCs and hiPSCs.

In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes. There are no effective approaches to preventing its development in the clinic. Long noncoding RNAs (lncRNA) are increasingly recognized as important molecular players in cardiovascular disease. Herein we investigated the profiling of cardiac lncRNA and mRNA expression in type 2 diabetic db/db mice with and without early diabetic cardiomyopathy. We found that db/db mice developed cardiac hypertrophy with normal cardiac function at 6 weeks of age but with a decreased diastolic function at 20 weeks of age. LncRNA and mRNA transcripts were remarkably different in 20-week-old db/db mouse hearts compared with both nondiabetic and diabetic controls. Overall 1479 lncRNA transcripts and 1109 mRNA transcripts were aberrantly expressed in 6- and 20-week-old db/db hearts compared with nondiabetic controls. The lncRNA-mRNA co-expression network analysis revealed that 5 deregulated lncRNAs having maximum connections with differentially expressed mRNAs were BC038927, G730013B05Rik, 2700054A10Rik, AK089884, and Daw1. Bioinformatics analysis revealed that these 5 lncRNAs are closely associated with membrane depolarization, action potential conduction, contraction of cardiac myocytes, and actin filament-based movement of cardiac cells. This study profiles differently expressed lncRNAs in type 2 mice with and without early diabetic cardiomyopathy and identifies BC038927, G730013B05Rik, 2700054A10Rik, AK089884, and Daw1 as the core lncRNA with high significance in diabetic cardiomyopathy.

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (iPSC-CMs) are a promising cell source for myocardial regeneration, disease modeling and drug assessment. However, iPSC-CMs exhibit immature fetal CM-like characteristics that are different from adult CMs in several aspects, including cellular structure and metabolism. As an example, glycolysis is a major energy source for immature CMs. As CMs mature, the mitochondrial oxidative capacity increases, with fatty acid β-oxidation becoming a key energy source to meet the heart's high energy demand. The immaturity of iPSC-CMs thereby limits their applications. The aim of this study was to investigate whether the energy substrate fatty acid-treated iPSC-CMs exhibit adult CM-like metabolic properties. After 20 days of differentiation from human iPSCs, iPSC-CMs were sequentially cultured with CM purification medium (lactate+/glucose-) for 7 days and maturation medium (fatty acids+/glucose-) for 3-7 days by mimicking the adult CM's preference of utilizing fatty acids as a major metabolic substrate. The purity and maturity of iPSC-CMs were characterized via the analysis of: (1) Expression of CM-specific markers (e.g., troponin T, and sodium and potassium channels) using RT-qPCR, Western blot or immunofluorescence staining and electron microscopy imaging; and (2) cell energy metabolic profiles using the XF96 Extracellular Flux Analyzer. iPSCs-CMs (98% purity) cultured in maturation medium exhibited enhanced elongation, increased mitochondrial numbers with more aligned Z-lines, and increased expression of matured CM-related genes, suggesting that fatty acid-contained medium promotes iPSC-CMs to undergo maturation. In addition, the oxygen consumption rate (OCR) linked to basal respiration, ATP production, and maximal respiration and spare respiratory capacity (representing mitochondrial function) was increased in matured iPSC-CMs. Mature iPSC-CMs also displayed a larger change in basal and maximum respirations due to the utilization of exogenous fatty acids (palmitate) compared with non-matured control iPSC-CMs. Etomoxir (a carnitine palmitoyltransferase 1 inhibitor) but not 2-deoxyglucose (an inhibitor of glycolysis) abolished the palmitate pretreatment-mediated OCR increases in mature iPSC-CMs. Collectively, our data demonstrate for the first time that fatty acid treatment promotes metabolic maturation of iPSC-CMs (as evidenced by enhanced mitochondrial oxidative function and strong capacity of utilizing fatty acids as energy source). These matured iPSC-CMs might be a promising human CM source for broad biomedical application.

Aim: This study aims to investigate the altered expression signature of long non-coding RNAs, mRNAs and deregulated pathways related to diabetic cardiomyopathy disease pathogenesis., Method: We utilize the previously established in vitro diabetic cardiomyopathy model of human induced pluripotent stem cell-derived human cardiomyocytes to perform long non-coding RNA and mRNA expression analysis on glucose (11 mM), endothelin-1 (10 nM) and cortisol (1 µM) stimulated human induced pluripotent stem cell-derived human cardiomyocytes to interrogate diabetic cardiomyopathy associated RNA expression profile., Result: Out of 20,730 mRNAs and 40,173 long non-coding RNAs being screened, 2046 long non-coding RNAs and 1582 mRNAs were differentially regulated (fold change > 2, p < 0.05) between diabetic cardiomyopathy and control group, of which more than half were intergenic and antisense long non-coding RNAs. Most of the coding transcripts were associated with processes like inflammation, structural reorganization, metabolism, smooth muscle contraction, focal adhesion and repair contributing towards the development of diabetic cardiomyopathy. The subgroup analysis further revealed 411 long non-coding RNAs being co-expressed with neighbouring genes. However, our coding-non-coding co-expression analysis showed an overall 48,155 co-expression network connections. In addition to that, the long non-coding RNAs with highest network connections were profoundly enriched for focal adhesion, cell-matrix adhesion and muscle contraction., Conclusion: These results provide comprehensive data about the pathways and regulatory mechanisms associated with diabetic cardiomyopathy and indicate that long non-coding RNAs may play a crucial role in diabetic cardiomyopathy.

Aims: Previous studies indicate that nitric oxide derived from endothelial nitric oxide synthase (eNOS) serves as both trigger and mediator in anaesthetic cardiac preconditioning. The mechanisms underlying regulation of eNOS by volatile anaesthetics have not been fully understood. Therefore, this study examined the role of vascular endothelial growth factor (VEGF) in isoflurane cardiac preconditioning., Methods and Results: Wistar rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Isoflurane given prior to ischaemia/reperfusion significantly decreased myocardial infarct size from 60 ± 1% in control to 40 ± 3% (n = 8 rats/group, P < 0.05). The beneficial effects of isoflurane were blocked by neutralizing antibody against VEGF (nVEGF). Coronary arterial endothelial cells (ECs) alone or together with cardiomyocytes (CMs) were subjected to hypoxia/reoxygenation injury. The expression of VEGF and eNOS was analysed by western blot, and nitric oxide was measured by ozone-based chemiluminescence. In co-cultured CMs and ECs, isoflurane administered before hypoxia/reoxygenation attenuated lactate dehydrogenase activity and increased the ratio of phosphorylated eNOS/eNOS and nitric oxide production. The protective effect of isoflurane on CMs was compromised by nVEGF and after VEGF in ECs was inhibited with hypoxia inducible factor-1α short hairpin RNA (shRNA). The negative effect of hypoxia inducible factor-1α shRNA was restored by recombinant VEGF., Conclusion: Isoflurane cardiac preconditioning is associated with VEGF regulation of phosphorylation of eNOS and nitric oxide production.

Despite considerable advances in medicine, cardiovascular disease is still rising, with ischemic heart disease being the leading cause of death and disability worldwide. Thus extensive efforts are continuing to establish effective therapeutic modalities that would improve both quality of life and survival in this patient population. Novel therapies are being investigated not only to protect the myocardium against ischemia-reperfusion injury but also to regenerate the heart. Stem cell therapy, such as potential use of human mesenchymal stem cells and induced pluripotent stem cells and their exosomes, will make it possible not only to address molecular mechanisms of cardiac conditioning, but also to develop new therapies for ischemic heart disease. Despite the studies and progress made over the last 15 years on the use of stem cell therapy for cardiovascular disease, the efforts are still in their infancy. Even though the expectations have been high, the findings indicate that most of the clinical trials generally have been small and the results inconclusive. Because of many negative findings, there is certain pessimism that cardiac cell therapy is likely to yield any meaningful results over the next decade or so. Similar to other new technologies, early failures are not unusual and they may be followed by impressive success. Nevertheless, there has been considerable attention to safety by the clinical investigators because the adverse events of stem cell therapy have been impressively rare. In summary, although regenerative biology might not help the cardiovascular patient in the near term, it is destined to do so over the next several decades., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Long noncoding RNAs (lncRNAs) are endogenous RNA transcripts longer than 200 nucleotides which regulate epigenetically the expression of genes but do not have protein-coding potential. They are emerging as potential key regulators of diabetes mellitus and a variety of cardiovascular diseases. Diabetic cardiomyopathy (DCM) refers to diabetes mellitus-elicited structural and functional abnormalities of the myocardium, beyond that caused by ischemia or hypertension. The purpose of this review was to summarize current status of lncRNA research for DCM and discuss the challenges and possible strategies of lncRNA research for DCM. A systemic search was performed using PubMed and Google Scholar databases. Major conference proceedings of diabetes mellitus and cardiovascular disease occurring between January, 2014 to August, 2018 were also searched to identify unpublished studies that may be potentially eligible. The pathogenesis of DCM involves elevated oxidative stress, myocardial inflammation, apoptosis, and autophagy due to metabolic disturbances. Thousands of lncRNAs are aberrantly regulated in DCM. Manipulating the expression of specific lncRNAs, such as H19, metastasis-associated lung adenocarcinoma transcript 1, and myocardial infarction-associated transcript, with genetic approaches regulates potently oxidative stress, myocardial inflammation, apoptosis, and autophagy and ameliorates DCM in experimental animals. The detail data regarding the regulation and function of individual lncRNAs in DCM are limited. However, lncRNAs have been considered as potential diagnostic and therapeutic targets for DCM. Overexpression of protective lncRNAs and knockdown of detrimental lncRNAs in the heart are crucial for defining the role and function of lncRNAs of interest in DCM, however, they are technically challenging due to the length, short life, and location of lncRNAs. Gene delivery vectors can provide exogenous sources of cardioprotective lncRNAs to ameliorate DCM, and CRISPR-Cas9 genome editing technology may be used to knockdown specific lncRNAs in DCM. In summary, current data indicate that LncRNAs are a vital regulator of DCM and act as the promising diagnostic and therapeutic targets for DCM.

Mounting evidence has demonstrated that general anesthetics could induce acute neuroapoptosis in developing animals followed by long-term cognitive dysfunction, with the mechanisms remaining largely unknown. The aim of this study was to investigate the effect of the intravenous anesthetic propofol on the profiles of microRNAs (miRNAs) and messenger RNAs (mRNAs), and their interactive signaling networks in the developing mouse hippocampus. Postnatal day 7 (P7) mice were exposed to propofol for 3 hours. Hippocampi were harvested from both P7 (3 hours after exposure) and P60 mice for the analysis of the expression of 726 miRNAs and 24,881 mRNAs, and apoptosis. Long-term memory ability of P60 mice was analyzed using the Morris Water Maze. Propofol induced acute apoptosis in the hippocampus, and impaired memory function of mice. There were 100 altered mRNAs and 18 dysregulated miRNAs in the propofol-treated hippocampi compared with the intralipid-treated control tissues on P7. Bioinformatics analysis of these abnormally expressed genes on P7 indicated that 34 dysregulated miRNA-mRNA target pairs were related to pathological neurological and developmental disorder processes such as cell viability, cell morphology and migration, neural stem cell proliferation and neurogenesis, oligodendrocyte myelination, reactive oxygen species, and calcium signaling. Neonatal propofol exposure also resulted in the abnormal expression of 49 mRNAs and 4 miRNAs in P60 mouse hippocampi. Specifically, bioinformatics analysis indicates that among these dysregulated mRNAs and miRNAs, there were 2 dysregulated miRNA-mRNA targets pairs (Fam46a/miR-363-3p and Rgs3/miR-363-3p) that might be related to the effect of propofol on long-term cognitive function. Collectively, our novel investigation indicates that acute and long-term dysregulated miRNA-mRNA signaling networks potentially participate in propofol-induced developmental neurotoxicity.