Some miRNA signatures associated with the use of Etomidate and Propofol and their implications for cardiac surgery

Some miRNA signatures associated with the use of Etomidate and Propofol and their implications for cardiac surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Some miRNA signatures associated with the use of Etomidate and Propofol and their implications for cardiac surgery Shokoufeh Habibi Manesh, Tahere Seifi, Fatemeh Javaher Forooshzadeh, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6047179/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background A growing body of evidence indicates that the anesthetics Propofol and Etomidate are associated with neurotoxic effects and considerable cognitive impairment. The varying impacts of these anesthetic agents on miRNA expression have been validated. Nevertheless, the effects of these substances on the cardiovascular system and their potential side effects in humans remain inadequately understood. This study aims to examine the impact of Etomidate and Propofol anesthetics on the expression profiles of miRNA in patients who are undergoing cardiovascular surgery. Materials and Methods This research examined the expression levels of miR-21, miR-146, and miR-155 in blood cells prior to and following the administration of Etomidate and Propofol. Furthermore, the study examined the relationship between these specific microRNAs and various clinicopathological characteristics. Blood samples were obtained from 60 patients for each anesthetic agent at three time points: before surgery, immediately after surgery, and 24 hours postoperatively. Mononuclear cells were separated utilizing Ficoll reagent, RNA was extracted using Qiazol reagent, and Real-Time quantitative PCR was employed to assess expression levels. The primary outcomes measured were mortality rates in the ICU and hospital, while secondary outcomes encompassed the number of ICU- and hospital-free days observed up to seven days following surgery. Results The results indicate an increase in the expression levels of miR-146, a decrease in miR-21 expression, and no change in miR-155 expression. It is worth noting that while the differences observed were statistically significant, the variations in expression levels were minor. Within 24 hours post-surgery, miR-21 expression returned to the baseline level when propofol was administered prior to the procedure. Additionally, it is important to mention that miR-146 expression decreased 24 hours after surgery with Etomidate anesthesia, although this change was not statistically significant. A significant moderate inverse correlation was discovered between the expressions of miR-21 and miR-146. Furthermore, no clinical pathological issues were observed, and there was no association between the differentially expressed genes and the clinicopathological factors. Conclusion This research highlights the impact of Etomidate and Propofol on the expression of microRNAs associated with inflammation, heart failure, neurotoxicity, cognitive dysfunction, and learning difficulties. Based on clinicopathological features, there is no discernible preference for either Propofol or Etomidate for anesthesia. With achieved results showing downregulation of miR-21 and upregulation of miR-146a, it is interesting to monitor patients over time. This underscores the importance of monitoring neurotoxicity, cognitive function, and learning capabilities following surgery. Figures Figure 1 Introduction Etomidate and Propofol have been the most widely used anesthetic drugs for imaging and surgical applications for many years [ 1 ]. Etomidate, a derivative of carboxylated imidazole, is often used as a general anesthetic and sedative because of its ultrashort duration of action [ 2 ]. To achieve its anesthetic effects, it binds to specific sites on the γ-aminobutyric acid type A receptor, which may lead to adrenotoxicity and cognitive impairment. However, the suitability of Etomidate for anesthesia induction remains a topic of active debate [ 3 ]. Propofol is a short-acting anesthetic frequently used for the induction and maintenance of anesthesia in both pediatric and adult populations. However, its use is associated with neurotoxicity, which remains a significant concern [ 4 , 5 ]. Additionally, anesthetic agents exhibit negative inotropic and vasodilatory effects that depend on the dosage administered [ 6 ]. These studies address important safety concerns regarding the use of anesthetics in the general public and highlight the significance of identifying biomarkers that can predict the side effects and outcomes of anesthesia. MicroRNAs (miRNAs) are emerging as valuable candidates for use as biomarkers for a range of conditions, including disorders of the nervous and cardiovascular systems. MiRNAs are small, non-coding RNA molecules typically measuring 20–22 nucleotides in length. They play a crucial role in the post-transcriptional regulation of mRNA expression, influencing various physiological processes such as cellular development, proliferation, differentiation, metabolism, and homeostasis [ 7 – 11 ]. Etomidate and Propofol exhibit different influences on the expression of cardiovascular miRNAs [ 7 ]. Experimental findings utilizing both in vivo and in vitro models indicate a downregulation of miR-21 following Propofol treatment, which is linked to neuronal cell death potentially via the STAT3-miR-21-Sprouty 2-Akt signaling pathway [ 12 ]. Additionally, miR-146a is significantly involved in the advancement of Alzheimer's disease (AD) through the miR-146a/STAT1/MYC pathway. The expression levels of miR-146a are associated with cognitive deficits in Alzheimer's disease [ 13 – 17 ]. This condition presents a significant risk for patients who have been exposed to anesthetics. Furthermore, the anti-inflammatory properties of Propofol are demonstrated by the knockdown of miR-155, a key regulator of neuroinflammation through IRF2BP2-NFAT1 pathway, in cells treated with LPS [ 18 ]. This research aims to investigate, for the first time, the effects of Etomidate and Propofol on the expression levels of miR-21, miR-146a, and miR-155 during the peri-anesthesia period, immediately following anesthesia, and 24 hours post-surgery. Moreover, the study will assess the correlation between differentially expressed genes and various clinicopathological features. The study aimed to compare Propofol- with Etomidate-based sedation following heart surgery, assessing primary outcomes such as ICU and hospital mortality, as well as secondary outcomes including the number of ICU- and hospital-free days over a period of 7-days. Material and Methods Study Population This study involved Iranian patients who participated in a research project focusing on those who received Etomidate and Propofol anesthesia during cardiac surgical procedures. Exclusions were applied to patients who had a confirmed acute myocardial infarction indicated by troponin-I (TnI) levels surpassing the 99th percentile before the surgical procedure, those with clinically diagnosed pulmonary embolism, and individuals receiving renal replacement therapy. The research adhered to the ethical guidelines outlined in the Declaration of Helsinki and was approved by Ethical Committee Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. (IR.AJUMS.REC.1400.103). Patients divided in two groups administrated with 1.5 mg/kg Propofol (Cat num. 0357HM0058), and 0.2 mg/kg Etomidate (cat num. NDC 25021-674-10). Anesthesia protocol Following the approval of the proposal and the acquisition of consent from the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences in Iran, as well as informed consent from the participants, individuals eligible for open coronary artery bypass grafting (CABG) were recruited for the study at Golestan Hospital in Ahvaz. After the patients were briefed on the procedures, an anesthesiologist conducted assessments to classify them into ASA classes II-III. A secure intravenous line was established, and the patients were subsequently transported to the operating room for the surgical procedure. Upon their arrival, standard monitoring protocols were implemented, which included five-lead electrocardiography, pulse oximetry, and the placement of an arterial line for the continuous assessment of blood pressure and blood gases. Following pre-oxygenation, the patients were allocated into two distinct groups for anesthesia induction: the Propofol group, serving as the control, and the Etomidate group, designated as the intervention. A standardized anesthesia protocol was implemented for all patients involved in the study. The dosages of anesthetic agents were determined according to the body weight of each patient. Anesthesia induction included midazolam at a dosage of 0.1 mg/kg, fentanyl at 15 µg/kg, and Propofol at 1.5 mg/kg for the control group, while the intervention group received Etomidate at 0.2 mg/kg, along with Cisatracurium at 0.3 mg/kg for muscle relaxation. Anesthesia maintenance was achieved through a continuous infusion of fentanyl at 4 µg/kg/h, midazolam at 0.25 mg/kg/h, and cisatracurium at 0.3 mg/kg/h until the conclusion of the surgical procedure. Following the induction of general anesthesia, a central venous catheter was inserted. For the commencement of cardiopulmonary bypass, all patients received a heparin dose of 350 u/kg, with adjustments made to achieve a target activated clotting time (ACT) of 450–480s. Upon completion of the bypass, protamine was administered at a rate of 1 mg for every 100 units of heparin to counteract its effects. Both the cardiac surgery and the subsequent postoperative care adhered to a uniform protocol. After the surgical intervention, all patients were moved to the cardiovascular intensive care unit, where a standardized protocol for sedation, analgesia (utilizing propofol at 0.5 mg/kg/h and morphine sulfate at 0.1 mg/kg/h), and management of mechanical ventilation in synchronized intermittent mandatory ventilation (SIMV) mode was established. Blood samples were received at the following times: T0 before surgery, T1 after termination of CPB, and T2 24 hours after the operation. Weaning from the ventilator was performed based on the following criteria: being responsive and cooperative, having a pO2 of 80–100, an oxygenation index of pO2/FiO2 > 300, and maintaining hemodynamic stability without the use of any inotrope Sample preparation Blood samples were collected before the surgical procedure, immediately after the operation, and one day post-surgery. A total of five milliliters of whole blood was drawn into a plain tube, allowed to clot at room temperature, and then centrifuged at 3500 x g for 10 minutes. The serum obtained was utilized for biochemical analysis. Additionally, mononuclear blood cells were isolated from 2 milliliters of blood using ficoll reagent. These samples were then frozen at -70°C for subsequent RNA extraction. microRNA isolation The patients were categorized into two distinct groups: one group received an injection of Etomidate, while the other group was administered Propofol. Blood samples were obtained from each participant at three different time points. Mononuclear cells were isolated using Ficoll reagent. Total RNA was extracted using Qiazol reagent in accordance with the manufacturer's guidelines. The quality and quantity of RNA were assessed through electrophoresis on a 1% agarose gel and with a NanoDrop instrument (Thermo Scientific™ NanoDrop™ One Microvolume UV-Vis Spectrophotometers). Subsequently, cDNA was synthesized from 2 µg of total RNA using the BONmiR High Sensitivity MicroRNA 1st Strand cDNA Synthesis kit (Bon Yakhteh Company, Tehran, Iran). The expression levels of miR-21, miR-146a, and miR-155 were quantified using qRT-PCR, with the specific primer purchased from Bon Yakhteh Company, Tehran, Iran. The RT-PCR reactions were performed in a total volume of 20 µL, comprising 10 µL of SYBR Green Master Mix (Yekta Tajhiz, Tehran, Iran), 2 µL of cDNA, and 0.6 µL each of the forward and reverse primers (10 µM). The q-RT PCR protocol included one cycle at 94°C for 1 minute, followed by 40 cycles of denaturation at 94°C for 10 seconds and annealing/extension at 60°C for 30 seconds. The U6 primer served as the internal control. Statistical analysis All data are presented as means ± standard deviation (SD). The Wilcoxon test was employed to compare differences between the two data groups. For the correlation analysis of relative gene expression with clinical parameters, Spearman's rank correlation coefficient was used. All analyses were conducted using GraphPad Prism Software Version 9. A p-value of less than 0.05 was deemed statistically significant. Statistically significant differences are indicated by asterisks (* p < 0.05, ** p < 0.01, *** p < 0.001). Results A comparative analysis of the expression levels of miR-21, miR-146, and miR-155 genes was conducted between treatments with Etomidate and Propofol. The expression of miR-21 was notably downregulated with fold changes of T1 = 0.87 ± 0.167 (P = 0.026) for Etomidate and T1 = 0.77 ± 0.174 (P = 0.005) for Propofol treatments, observed both postoperatively and 24 hours following surgery, with fold changes recorded as T2 = 0.86 ± 0.81 (P = 0.037), T2 = 0.88 ± 0.14 (P = 0.036), respectively. Conversely, miR-146 exhibited an upregulation, with fold changes of T1 = 1.48 ± 0.63 (P = 0.025) for Etomidate and T1 = 1.51 ± 0.43 (p = 0.004) for Propofol. Statistical evaluations indicated significant differences in expression levels postoperatively for Etomidate and Propofol (P = 0.025, P = 0.004, respectively). Although no significant differences were noted at the 24-hour post-surgery for Etomidate: T2 = 1.24 ± 0.488 (p = 0.086), and But, it is induction with propofol is significant; T2 = 1.6 ± 0.79 (P = 0.045) (Fig. 1 ). Notably, the expression levels of miR-155 did not exhibit any significant variations between the two treatment modalities: T1 = 0.94 ± 0.19 (P = 0.189) and T2 = 0.96 ± 0.35 (P = 0.35) for Etomidate and T1 = 0.90 ± 0.43 (p = 0.004), and T2 = 0.99 ± 0.49 (P = 0.48) for Propofol. The comparative analysis of miR-21, miR-146, and miR-155 expression is depicted in Fig. 1 , both in the postoperative period and 24 hours following the surgical procedure. The association between the expressions of differentially expressed genes was examined by utilizing the fold change ratio for each gene to determine the correlation coefficient. A negative correlation was observed between the expressions of miR-21 and miR-146 in T1 (r = -0.65; moderate; p = 0.025) and in T2 (r = -0.2; weak; p = 0.166). The association between gene expression in patients receiving propofol and etomidate anaesthesia and their clinicopathological characteristics was examined . The analysis revealed no significant correlation between the levels of differentially expressed genes and various clinicopathological factors, including sex, age, body mass index (BMI), challenges in isolation during the ICU stay, as well as SGOT and SGPT levels in the patients (Table I, Table II). Table I: Association between expression of the selected genes and clinicopathological characteristics of patients anesthetized with Etomidate. miR-155 miR-146 miR-21 n/ percentage T2 T1 T2 T1 T1 T1 0.32 -0.30 -0.09 -0.31 -0.23 0.60 58 % 42 % Sex Male Female -0.31 -0.16 0.35 -0.13 -.60 -0.17 45-75 Age (Years) 0.84 0.28 0.50 0.05 -0.59 -0.17 M: 25.3-29.5 F: 25.5-33.3 BMI 0.3 -0.30 0.81 0.73 -0.48 -0.59 F: 57% (-)/ 43% (+) M: 60% (-)/ 40% (+) hard to isolation from pump 0.2 -0.14 0.53 0.72 -0.59 0.25 F: 57 (2)/28.8 (3)/14.2 (4) 60% (2)/ 20% (3)/ 20% (4) ICU stay (x days) 0.36 0.32 0.02 -0.03 0.38 0.23 F: 22-33 M: 16-29 SGOT -0.02 0.13 0.02 -0.03 0.57 -0.19 F: 23-51 M: 20-41 SGPT Table II: Association between expression of the selected genes and clinicopathological characteristics of patients anesthetized with propofol. miR-155 miR-146 miR-21 n/ percentage T2 T1 T2 T1 T2 T1 -0.2 -0.08 -0.31 -0.53 -0.46 -0.36 62% 38% Sex Male Female 0.20 0.35 0.04 -0.14 -0.09 -0.71 41-87 Age 0.14 -0.27 0.55 -0.05 -0.36 0.33 M: 26-33 F: 24.5-28 BMI -0.54 -0.38 -0.50 -0.25 -0.34 -0.19 M: 75% (-)/ 25% (+) F: 34% (-)/ 66% (+) hard to isolation from pump 0.11 0.22 -0.07 0.04 0.68 -0.02 M: 69% (2)/31% (3) * F: 50% (2)/ 50% (3) + ICU stay (x days) -0.00 0.28 -0.38 -0.57 0.33 -0.36 M: 20-25 F: 24-25 + SGOT -0.00 0.31 -0.38 -0.63 -0.55 -0.60 M: 20-28 F: 22-26 + SGPT 1 male patient stayed at ICU for 14 days 1 female patient stayed at ICU for 5 days; SGOT: 83 , and SGPT: 75 * + Discussion Etomidate and Propofol are both agents used for general anesthesia, each exhibiting distinct effects on several parameters. These parameters encompass myocardial function, blood pressure, heart rate, and intubation, which are regarded as primary outcomes. Furthermore, myoclonic movements, along with postoperative nausea and vomiting, are classified as secondary outcomes [ 19 – 20 ]. This study aimed to assess the impact of Propofol and Etomidate on miRNA related to inflammation and neurotoxicity in blood cells among individuals undergoing these surgical interventions for the first time. It also sought to investigate the correlation of differentially expressed genes (DEGs) with various clinicopathological factors, including age, sex, body mass index (BMI), difficulties in ICU isolation, and levels of SGOT and SGPT as markers of inflammation and hepatotoxicity. Additionally, epinephrine and norepinephrine were examined as markers of inflammation and indicators of neurotoxicity. Previous studies have reported that the administration of etomidate in cirrhotic patients with sepsis results in an exceedingly high 28-day mortality rate, and an increase in ICU mortality [ 20 ]. Additionally, the well-known anti-inflammatory and antioxidant effects of Propofol in surgical trauma are significant [ 21 ]. Propofol has been shown to reduce neuroinflammation associated with surgery in mouse models, leading to a decrease in accelerated Alzheimer's neuropathology and symptoms compared to volatile anesthesia [ 21 – 23 ]. It is crucial to assess the effects of Etomidate and Propofol on key molecular biomarkers. The current research focuses on the expression levels of miR-21-5p, miR-146a-5p, and miR-155. These microRNAs regulate inflammatory responses, inflammation suppression, and antidepressant responses in various diseases such as neurological disease, autoimmune disease, cancer, and infectious diseases, according to investigations [ 24 – 27 ]. The downregulation of miR-21 is linked to neuronal death, and its overexpression plays a protective role in keeping neurons safe [ 12 , 28 – 30 ] while the upregulation of miR-146a is associated with the progression of Alzheimer’s disease and cognitive impairment [ 13 – 16 ]. Additionally, miR-155 may serve as a potential biomarker for heart failure and neuroinflammation. This evaluation will help in selecting a safer induction agent and determining suitable dosages to manage primary outcomes, as well as safeguarding patients against potential secondary outcomes. We found that: 1) Patients undergoing anesthesia induction with Propofol and Etomidate during cardiac surgery demonstrate a significant decrease in miR-21 expression after the procedure. The level of miR-21 under treatment with Propofol approximately returns to baseline within the first 24 hours post-surgery, 2) The expression of miR-146 was found to be elevated following surgery within a 24-hour period, 3) the expression levels of miR-155 were not influenced by exposure to Propofol and Etomidate, 4) The association analysis indicated a notable moderate correlation between miR-21 and miR-146a, which is introduced as inflammaging miRs by studies performed during “epigenetic revolution" [ 31 ]. 5) no correlation was identified between these differentially expressed genes and the clinicopathological characteristics. 6) Etomidate and Propofol show no significant differences in either primary or secondary clinical outcomes, 7) Based on our results regarding miR-21 and miR-146a expression, it is assumed that Propofol and Etomidate, respectively, show no preferences for the selection of anesthetic agents in enrolled patients. However, based on the variation in the genetic background of studied patients, these data can be influenced. We can conclude that more studies and monitoring of patients are needed for substantial preferences in the selection of anesthetic agents. Based on clinicopathological features, there are no substantial preferences in the selection of anesthetic agents when comparing Etomidate to Propofol. It is worth note that anti-inflammatory effect of Propofol is known and the neuroinflammation associated with surgery, leading to accelerated Alzheimer's neuropathology and symptoms, is reduced by Propofol compared with volatile anesthesia [ 23 ]. We consistently noted that among our patients undergoing on cardiothoracic surgery there were no clinical complications linked to SGOT, SGPT, epinephrine, norepinephrine, intubation levels, duration of ICU stay, or ICU mortality within a seven-day timeframe after the administration of Etomidate and Propofol (Table I, II). Research highlighted the hepatotoxic effects of Propofol under hypoxic conditions in rat models. Also, it was found that Propofol protects the liver, kidney, and heart in rats with sepsis by inhibiting HMGB1 expression [ 32 – 33 ]. Data from in vivo studies indicate that a duration of 5–6 hours of Propofol exposure, which is essential for sustaining surgical anesthesia, resulted in significant neuroapoptosis in both fetal and primate models. Furthermore, a 5-hour exposure to Propofol was associated with cell death in neonatal rat hippocampal neurons. In addition, an increase in activated caspase-3 levels was observed immediately after exposure in 7-day-old rats [ 34 – 36 ]. In a pioneering in vitro study, Twaroski et al. (2024) revealed that even a clinically relevant dose of Propofol administered over 6 hours led to substantial cell death in neurons derived from 2-week-old human embryonic stem cells [ 12 ]. They found that the downregulation of miR-21 following Propofol exposure may have contributed to neuronal cell death, potentially through the STAT3-miR-21-Sprouty 2-Akt signaling pathway [ 12 ]. Our research indicates that patients undergoing anesthesia induction with Propofol and Etomidate during cardiac surgery demonstrate a significant decrease in miR-21 expression after the procedure. We further underline that an expression decreasing is significantly more pronounced by Propofol induction compared to Etomidate. The level of miR-21 under treatment with Propofol is returning to baseline within the first 24 hours post-surgery. The restoration of expression levels within 24 hours may contribute to alleviating potential neurotoxic effects; however, careful monitoring remains essential due to the risk of both irreversible and reversible neurotoxic adverse effects. This is particularly important as we lack data regarding the duration required for neurotoxicity associated with Propofol or Etomidate in humans, which can vary based on genetic differences. Additionally, the signaling pathways related to miR-21 warrant further investigation, and the existence of interconnected expression networks should also be considered. Inconsistent with earlier studies. Our biochemical analyses reveal that the expression of miR-21 does not correlate with factors such as sex, age, BMI, difficulties in isolation from the ICU stay, or levels of SGOT, SGPT, epinephrine, or norepinephrine. Conversely, the expression of miR-146a was found to be elevated following surgery. It was returning to baseline levels 24 hours after surgery when Etomidate was administered. However, the expression of miR-146 increased significantly when Propofol was administered during this time. To the best of our knowledge, this study is the first to investigate miR-146a expression in patients treated with Propofol and Etomidate after cardiac surgery. Saba et al. (2014) identified miR-146a as a crucial negative regulator of the innate immune response [ 15 ]. In 2020, Fan et al. emphasized that microRNA-146a acts as a significant regulator of neuroinflammation and represents a potential therapeutic target for neurological disorders, highlighting its potential as both a biomarker and a treatment target [ 16 ]. Furthermore, Gomes et al. (2022) demonstrated that the depletion of miR-146a in neurotoxic astrocytes from ALS patients could provide therapeutic advantages [ 17 ]. Additionally, Ma et al. (2021) indicated that miR-146a is instrumental in the progression of Alzheimer's disease through the miR-146a/STAT1/MYC pathway [ 13 ]. Additionally, miR-146a expression has been linked to cognitive dysfunction in Alzheimer's disease [ 14 – 17 ]. Our findings, consistent with prior data, indicate for the first time an upregulation of miR-146a expression following the administration of Propofol and Etomidate. Notably, there is no observed correlation between miR-146a expression and various clinicopathological factors, including sex, age, BMI, challenges in isolation from the ICU, or levels of SGOT, SGPT, epinephrine, or norepinephrine. This lack of correlation may be attributed to the complex interconnections within the gene expression network. It is crucial to highlight that we currently lack information regarding the duration required for neurotoxicity linked to Propofol or Etomidate in humans in relation to miR-146 expression. This underscores the necessity for studies employing human stem cell-derived neurons as a model, particularly focusing on cells derived from individual patients. Additionally, there is an urgent requirement for further research into the signaling pathways related to miR-146; however, it is also important to take into account the presence of interconnected expression networks. It is noteworthy that the expression levels of miR-155 were not influenced by exposure to Propofol and Etomidate, which may further support a potential link to the absence of heart failure after the surgical procedure. Experimental findings have demonstrated that the anti-inflammatory properties of Propofol are diminished by the knockdown of miR-155 in cells treated with Lipopolysaccharide, operating through the IRF2BP2-NFAT1 pathway, as well as through the miR-155/SOCS1 mechanism in cases of acute lung injury and microglial activity, respectively [ 18 ]. It is crucial to emphasize that we currently lack data on the duration necessary for neurotoxicity and neuroinflammation associated with Propofol or Etomidate in humans concerning miR-155 expression. This highlights the need for investigations utilizing in vitro , in vivo , and particularly ex vivo models. Furthermore, there is an immediate necessity for additional research into the signaling pathways associated with miR-155; however, it is equally important to consider the existence of interconnected expression networks as previously mentioned. The association analysis indicated a notable moderate correlation between miR-21 and miR-146a, which is introduced as inflammaging miRs by studies performed during “epigenetic revolution" [ 31 ]. Nevertheless, no correlation was identified between these differentially expressed genes and the clinicopathological characteristics. It has been noted that Etomidate affects adrenal suppression in patients suffering from sepsis and is linked to clinically significant transient hypotension when compared to other sedatives. However, this did not result in statistically significant differences in the secondary clinical outcomes [ 37 ]. Etomidate increases epinephrine levels by inhibiting its metabolism, which makes its use contraindicated. Nonetheless, no interactions were found between Adrenaline and Propofol. It is important to highlight that this does not rule out the possibility of potential interactions. In 2006, Niwa et al. suggested that Propofol might mitigate the increased cardiovascular response triggered by epinephrine [ 38 ]. Our study indicated that the use of Etomidate and Propofol does not affect adrenal function. Furthermore, our investigation reveals that Etomidate and Propofol show no significant differences in either primary or secondary clinical outcomes. We have determined that there are no substantial preferences in the selection of anesthetic agents for adults be when comparing Etomidate to Propofol. Both agents affect the expression of miR-21 and miR-146, which are essential in the context of neurotoxicity and neuroinflammation related to cognitive dysfunction and the progression of Alzheimer’s disease. The notable limitation of this study may be the inadequate duration of patient monitoring. Additionally, the second limitation is that we assessed the expression of microRNAs (miRs) and certain clinical parameters as the final endpoints. These agents may have molecular effects that could impact long-term outcomes, such as elevated intracellular ion levels, including calcium, and disrupted cell signaling. The third limitation is that research involving human subjects was limited to blood cells. It is important to note that ex vivo models can be utilized to examine the effects of anesthesia. In conclusion, this is the first time that microRNA-21, 146 and 155 expression in the Anesthetic Propofol and Etomidate has been studied. The observed downregulation and upregulation in the blood cells of patients following exposure to Propofol and Etomidate may potentially lead to cognitive impairments and learning difficulties, as evidenced by animal studies. Ultimately, the identification of the altered expression patterns of miR-21 and miR-146 during anesthesia induced by Propofol and Etomidate could open avenues for future research focused on patient monitoring and the development of neuroprotective strategies. Therefore, we advocate for the use of microarray, RNA-seq analyses, and epigenomic studies to investigate microRNA networks, particularly with a focus on cardiac muscle or blood transcriptomes. Additional research should be conducted utilizing in vitro and ex vivo cell culture methodologies and gene knockdown techniques targeting relevant factors associated with drug responsiveness. Declarations Ethics statement The studies involving humans were approved by Ethical Committee Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. (IR.AJUMS.REC.1400.103). Informed consent was obtained from all enrolled patients. The studies were conducted in accordance with the local legislation and institutional requirements (Research project number: PAIN-0003). Written informed consent for participation in this study was provided by the participants, also, written informed consent was obtained from the individuals included in this article (Supplementary data). Data availability statement The datasets presented in this article cannot be publicly shared due to privacy restrictions. Requests to access the datasets should be directed to the corresponding authors. Author Contributions FJ and HG: conceived and designed the study, obtained funding, developed methodology, performed statistical analyses and interpretation of data, reviewed, and revised the manuscript. TS: designed the study, data analysis, bioinformatics and in silico study and writing–original draft. SH, NB, MB: Molecular and cellular techniques, MH: statically analysis. TS. FJ, HG, NB, MB and MH: reviewed and edited. Coauthors read and accepted the manuscript. All authors contributed to the article and approved the submitted version. Funding The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. Acknowledgment We grateful to the staff of Golestan hospital and all enrolled patients. Conflict of interest 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. References Lu Z, Zheng H, Chen Z, et al. Effect of etomidate vs propofol for total Intravenous anesthesia on major postoperative complications in older patients: a randomized clinical trial. JAMA surg. 2022;157(10):888–95. Forman SA. 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Zingale VD, Gugliandolo A, Mazzon E. MiR-155: An Important Regulator of Neuroinflammation. Int J Mol Sci. 2021;23(1):90. Cherfan AJ, Tamim HM, AlJumah A et al. Etomidate and mortality in cirrhotic patients with septic shock. BMC Clin Pharmacol. 2011:1–8. Aggarwal S, Goyal VK, Chaturvedi SK, Mathur V, Baj B, Kumar A. A comparative study between propofol and etomidate in patients under general anesthesia. Braz J Anesthesiol. 2016;66:237–41. Roh GU, Song Y, Park J, Ki YM, Han DW. Effects of propofol on the inflammatory response during robot-assisted laparoscopic radical prostatectomy: a prospective randomized controlled study. Sci Rep. 2019;9(1):5242. Mardini F, Tang JX, Li JC, Arroliga MJ, Eckenhoff RG, Eckenhoff MF. Effects of propofol and surgery on neuropathology and cognition in the 3xTgAD Alzheimer transgenic mouse model. BJA: Br J Anaesth. 2017;119(3):472–80. Hung YY, Chou CK, Yang YC, Fu HC, Loh EW, Kang HY. Exosomal let-7e, miR-21-5p, miR-145, miR-146a and miR-155 in Predicting Antidepressants Response in Patients with Major Depressive Disorder. Biomedicines. 2021;9(10):1428. Rajabi S, Sadegi K, Hajisobhani S, Kaveh M, Taghizadeh E. miR-146a and miR-155 as promising biomarkers for prognosis and diagnosis of multiple sclerosis: systematic review. Egypt J Med Hum Genet. 2024;25(1):73. Wang D, Wang X, Song Y, et al. Exosomal miR-146a-5p and miR-155-5p promote CXCL12/CXCR7-induced metastasis of colorectal cancer by crosstalk with cancer-associated fibroblasts. Cell Death Dis. 2022;13(4):380. Gaytán-Pacheco N, Ibáñez-Salazar A, Herrera-Van Oostdam AS, et al. miR-146a, miR-221, and miR-155 are Involved in Inflammatory Immune Response in Severe COVID-19 Patients. Diagnostics (Basel). 2022;13(1):133. Yan H, Huang W, Rao J, Yuan J. miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway. Aging. 2021;13(18):22242. Buller B, Liu X, Wang X, et al. MicroRNA-21 protects neurons from ischemic death. FEBS J. 2010;277(20):4299–307. Zhang T, Ni S, Luo Z, Lang Y, Hu J, Lu H. The protective effect of microRNA-21 in neurons after spinal cord injury. Spinal Cord. 2019;57(2):141–9. Olivieri F, Prattichizzo F, Giuliani A, et al. miR-21 and miR-146a: the microRNAs of inflammaging and age-related diseases. Ageing Res Rev. 2021;70:101374. Abdel-Wahab AF, Al-Harizy WM. Propofol protects against ischemia/reperfusion injury associated with reduced apoptosis in rat liver. Int Sch Res Notices. 2013;2013(1):517478. Bao HG, Li S. Effects of propofol on the outcomes of rats with sepsis. J Surg Res. 2011;168(1):e111–5. Bosnjak ZJ, Logan S, Liu Y, Bai X. Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies. Anesth Analg. 2016;123(5):1286–96. Li Y, Jia C, Zhang D, Ni G, Miao X, Tu R. Propofol-induced neurotoxicity in hESCs involved in activation of miR-206/PUMA signal pathway. Cancer Biomark. 2017;20(2):175–81. Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth. 2013;110(suppl1):i29–38. Thompson Bastin ML, Baker SN, Weant KA. Effects of etomidate on adrenal suppression: a review of intubated septic patients. Hosp Pharm. 2014;49(2):177–83. Niwa H, Tanimoto A, Sugimura M, Morimoto Y, Hanamoto H. Cardiovascular effects of epinephrine under sedation with nitrous oxide, propofol, or midazolam. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and En. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6047179","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":421953845,"identity":"63677944-1075-4852-acc9-5de1d11e720d","order_by":0,"name":"Shokoufeh Habibi Manesh","email":"","orcid":"","institution":"Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz","correspondingAuthor":false,"prefix":"","firstName":"Shokoufeh","middleName":"Habibi","lastName":"Manesh","suffix":""},{"id":421953846,"identity":"f8b59b8a-a4f7-448b-be76-a2f8b536f900","order_by":1,"name":"Tahere Seifi","email":"","orcid":"","institution":"Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz","correspondingAuthor":false,"prefix":"","firstName":"Tahere","middleName":"","lastName":"Seifi","suffix":""},{"id":421953851,"identity":"ccd67119-96ae-458e-9208-e05233e65d4e","order_by":2,"name":"Fatemeh Javaher Forooshzadeh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYBAC9gaGBCB1gIGB+QBYIIGfgYENrxaeAzAtbAkQLZINhLUwoGoxOEBICwPDw888NXfkzNuYj334UFGXZ3wj+dmDDxUM8vxiB3BpSZbmOfbMWOYYW/LMGWcOF5vdSDM3nHGGwXDm7ASsWuxBrp/BdjhxhnyPMTNv24HEbTcSzKR524AuvI1dC8iWnzP+Ha6fwcYD0lKXuHlG+jdCWtIkPrYdTpCAaGFO3CCRQ9CWNIuPfYcNZ7CxJTMC/ZI448ybMskZZyRw+oWHgSf5RsK3w/ISbMyHGYAhltjfnr5N4kOFjTy/NHYtDPJv0CUEwAIS2JWDAfsBNAF+dIFRMApGwSgY6QAAhENdNtjzKv8AAAAASUVORK5CYII=","orcid":"","institution":"Department of Anesthesia, Pain Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz","correspondingAuthor":true,"prefix":"","firstName":"Fatemeh","middleName":"Javaher","lastName":"Forooshzadeh","suffix":""},{"id":421953853,"identity":"acf58f86-8df8-4397-850d-8235b7a98eb3","order_by":3,"name":"Hamid Galehdari","email":"","orcid":"","institution":"Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz","correspondingAuthor":false,"prefix":"","firstName":"Hamid","middleName":"","lastName":"Galehdari","suffix":""},{"id":421953856,"identity":"b46d0bcf-9fb1-4e7e-8e7f-5c2f60aaa64b","order_by":4,"name":"Nima Bakhtiari","email":"","orcid":"","institution":"Ahvaz Anesthesiology and Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz","correspondingAuthor":false,"prefix":"","firstName":"Nima","middleName":"","lastName":"Bakhtiari","suffix":""},{"id":421953860,"identity":"de4afd0d-b850-4426-b3af-7f43cdadb3b3","order_by":5,"name":"Marzieh Baba zadeh","email":"","orcid":"","institution":"Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz","correspondingAuthor":false,"prefix":"","firstName":"Marzieh","middleName":"Baba","lastName":"zadeh","suffix":""},{"id":421953862,"identity":"7f27f164-2ff0-44a1-aab2-4d2397e48184","order_by":6,"name":"Mohammad-Hosein Haghighizadeh","email":"","orcid":"","institution":"Department of Biostatistics and Epidemiology, School of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz","correspondingAuthor":false,"prefix":"","firstName":"Mohammad-Hosein","middleName":"","lastName":"Haghighizadeh","suffix":""}],"badges":[],"createdAt":"2025-02-17 10:53:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6047179/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6047179/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77682038,"identity":"245f0fed-64ee-4cfa-971c-dd4b2537a9c0","added_by":"auto","created_at":"2025-03-04 08:46:03","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181808,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA comparative analysis of the expression levels of miR-21, miR-146, and miR-155 genes was conducted between treatments with Etomidate and Propofol.\u003c/strong\u003e The comparative analysis of miR-21, miR-146, and miR-155 expression is depicted in the postoperative period and 24 hours following the surgical procedure. (a) The expression of miR-21 was notably downregulated with fold changes of T1 = 0.87 ± 0.167 (P = 0.037) and T2 = 0.86 ± 0.81 (P = 0.037) for Etomidate and T1 = 0.77 ± 0.174 (P = 0.005) and T2 = 0.88 ± 0.14 (P = 0.036 for Propofol treatments, both postoperatively and 24 hours following surgery (b) Conversely, The expression of miR-146a was notably upregulated with fold changes of T1=1.48 ± 0.63 (P = 0.025) and T2= 1.24 ± 0.488 (p = 0.086) for Etomidate and T1= 1.51 ± 0.43 (p = 0.004) and T2= 1.24 ± 0.488 (p = 0.086) for Propofol treatments, both postoperatively and 24 hours following surgery (c) The expression levels of miR-155 did not exhibit any significant variations between the two treatment modalities: T1=0.94 ± 0.19 (P = 0.189) and T2 = 0.96 ± 0.35 (P = 0.35) for Etomidate and T1= 0.90 ± 0.43 (p = 0.004), and T2 = 0.99 ± 0.49 (P = 0.48)\u0026nbsp; for Propofol. The comparative analysis of miR-21, miR-146a, and miR-155 expression is depicted in Fig. 1, both in the postoperative period and 24 hours following the surgical procedure. Statistically significant differences are indicated by asterisks (*\u003csup\u003e,+\u003c/sup\u003e p \u0026lt; 0.05, **\u003csup\u003e,++\u003c/sup\u003e p \u0026lt; 0.01)\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6047179/v1/a3a4710dc69cb47cd383002e.jpg"},{"id":83892437,"identity":"f2ada40f-b041-417a-8828-448b94e02160","added_by":"auto","created_at":"2025-06-04 08:17:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1597415,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6047179/v1/c82a820c-94d9-4561-88e6-1a6171222953.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Some miRNA signatures associated with the use of Etomidate and Propofol and their implications for cardiac surgery","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEtomidate and Propofol have been the most widely used anesthetic drugs for imaging and surgical applications for many years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Etomidate, a derivative of carboxylated imidazole, is often used as a general anesthetic and sedative because of its ultrashort duration of action [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. To achieve its anesthetic effects, it binds to specific sites on the γ-aminobutyric acid type A receptor, which may lead to adrenotoxicity and cognitive impairment. However, the suitability of Etomidate for anesthesia induction remains a topic of active debate [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePropofol is a short-acting anesthetic frequently used for the induction and maintenance of anesthesia in both pediatric and adult populations. However, its use is associated with neurotoxicity, which remains a significant concern [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Additionally, anesthetic agents exhibit negative inotropic and vasodilatory effects that depend on the dosage administered [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese studies address important safety concerns regarding the use of anesthetics in the general public and highlight the significance of identifying biomarkers that can predict the side effects and outcomes of anesthesia. MicroRNAs (miRNAs) are emerging as valuable candidates for use as biomarkers for a range of conditions, including disorders of the nervous and cardiovascular systems. MiRNAs are small, non-coding RNA molecules typically measuring 20\u0026ndash;22 nucleotides in length. They play a crucial role in the post-transcriptional regulation of mRNA expression, influencing various physiological processes such as cellular development, proliferation, differentiation, metabolism, and homeostasis [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEtomidate and Propofol exhibit different influences on the expression of cardiovascular miRNAs [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Experimental findings utilizing both \u003cem\u003ein vivo\u003c/em\u003e and \u003cem\u003ein vitro\u003c/em\u003e models indicate a downregulation of miR-21 following Propofol treatment, which is linked to neuronal cell death potentially via the STAT3-miR-21-Sprouty 2-Akt signaling pathway [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Additionally, miR-146a is significantly involved in the advancement of Alzheimer's disease (AD) through the miR-146a/STAT1/MYC pathway. The expression levels of miR-146a are associated with cognitive deficits in Alzheimer's disease [\u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This condition presents a significant risk for patients who have been exposed to anesthetics. Furthermore, the anti-inflammatory properties of Propofol are demonstrated by the knockdown of miR-155, a key regulator of neuroinflammation through IRF2BP2-NFAT1 pathway, in cells treated with LPS [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis research aims to investigate, for the first time, the effects of Etomidate and Propofol on the expression levels of miR-21, miR-146a, and miR-155 during the peri-anesthesia period, immediately following anesthesia, and 24 hours post-surgery. Moreover, the study will assess the correlation between differentially expressed genes and various clinicopathological features. The study aimed to compare Propofol- with Etomidate-based sedation following heart surgery, assessing primary outcomes such as ICU and hospital mortality, as well as secondary outcomes including the number of ICU- and hospital-free days over a period of 7-days.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThis study involved Iranian patients who participated in a research project focusing on those who received Etomidate and Propofol anesthesia during cardiac surgical procedures. Exclusions were applied to patients who had a confirmed acute myocardial infarction indicated by troponin-I (TnI) levels surpassing the 99th percentile before the surgical procedure, those with clinically diagnosed pulmonary embolism, and individuals receiving renal replacement therapy. The research adhered to the ethical guidelines outlined in the Declaration of Helsinki and was approved by Ethical Committee Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. (IR.AJUMS.REC.1400.103). Patients divided in two groups administrated with 1.5 mg/kg Propofol (Cat num. 0357HM0058), and 0.2 mg/kg Etomidate (cat num. NDC 25021-674-10).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eAnesthesia protocol\u003c/strong\u003e \u003cp\u003e Following the approval of the proposal and the acquisition of consent from the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences in Iran, as well as informed consent from the participants, individuals eligible for open coronary artery bypass grafting (CABG) were recruited for the study at Golestan Hospital in Ahvaz.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eAfter the patients were briefed on the procedures, an anesthesiologist conducted assessments to classify them into ASA classes II-III. A secure intravenous line was established, and the patients were subsequently transported to the operating room for the surgical procedure. Upon their arrival, standard monitoring protocols were implemented, which included five-lead electrocardiography, pulse oximetry, and the placement of an arterial line for the continuous assessment of blood pressure and blood gases.\u003c/p\u003e \u003cp\u003eFollowing pre-oxygenation, the patients were allocated into two distinct groups for anesthesia induction: the Propofol group, serving as the control, and the Etomidate group, designated as the intervention.\u003c/p\u003e \u003cp\u003eA standardized anesthesia protocol was implemented for all patients involved in the study. The dosages of anesthetic agents were determined according to the body weight of each patient. Anesthesia induction included midazolam at a dosage of 0.1 mg/kg, fentanyl at 15 \u0026micro;g/kg, and Propofol at 1.5 mg/kg for the control group, while the intervention group received Etomidate at 0.2 mg/kg, along with Cisatracurium at 0.3 mg/kg for muscle relaxation. Anesthesia maintenance was achieved through a continuous infusion of fentanyl at 4 \u0026micro;g/kg/h, midazolam at 0.25 mg/kg/h, and cisatracurium at 0.3 mg/kg/h until the conclusion of the surgical procedure. Following the induction of general anesthesia, a central venous catheter was inserted. For the commencement of cardiopulmonary bypass, all patients received a heparin dose of 350 u/kg, with adjustments made to achieve a target activated clotting time (ACT) of 450\u0026ndash;480s. Upon completion of the bypass, protamine was administered at a rate of 1 mg for every 100 units of heparin to counteract its effects. Both the cardiac surgery and the subsequent postoperative care adhered to a uniform protocol. After the surgical intervention, all patients were moved to the cardiovascular intensive care unit, where a standardized protocol for sedation, analgesia (utilizing propofol at 0.5 mg/kg/h and morphine sulfate at 0.1 mg/kg/h), and management of mechanical ventilation in synchronized intermittent mandatory ventilation (SIMV) mode was established.\u003c/p\u003e \u003cp\u003eBlood samples were received at the following times: T0 before surgery, T1 after termination of CPB, and T2 24 hours after the operation. Weaning from the ventilator was performed based on the following criteria: being responsive and cooperative, having a pO2 of 80\u0026ndash;100, an oxygenation index of pO2/FiO2\u0026thinsp;\u0026gt;\u0026thinsp;300, and maintaining hemodynamic stability without the use of any inotrope\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSample preparation\u003c/h3\u003e\n\u003cp\u003eBlood samples were collected before the surgical procedure, immediately after the operation, and one day post-surgery. A total of five milliliters of whole blood was drawn into a plain tube, allowed to clot at room temperature, and then centrifuged at 3500 x g for 10 minutes. The serum obtained was utilized for biochemical analysis. Additionally, mononuclear blood cells were isolated from 2 milliliters of blood using ficoll reagent. These samples were then frozen at -70\u0026deg;C for subsequent RNA extraction.\u003c/p\u003e\n\u003ch3\u003emicroRNA isolation\u003c/h3\u003e\n\u003cp\u003eThe patients were categorized into two distinct groups: one group received an injection of Etomidate, while the other group was administered Propofol. Blood samples were obtained from each participant at three different time points. Mononuclear cells were isolated using Ficoll reagent. Total RNA was extracted using Qiazol reagent in accordance with the manufacturer's guidelines. The quality and quantity of RNA were assessed through electrophoresis on a 1% agarose gel and with a NanoDrop instrument (Thermo Scientific\u0026trade; NanoDrop\u0026trade; One Microvolume UV-Vis Spectrophotometers). Subsequently, cDNA was synthesized from 2 \u0026micro;g of total RNA using the BONmiR High Sensitivity MicroRNA 1st Strand cDNA Synthesis kit (Bon Yakhteh Company, Tehran, Iran). The expression levels of miR-21, miR-146a, and miR-155 were quantified using qRT-PCR, with the specific primer purchased from Bon Yakhteh Company, Tehran, Iran. The RT-PCR reactions were performed in a total volume of 20 \u0026micro;L, comprising 10 \u0026micro;L of SYBR Green Master Mix (Yekta Tajhiz, Tehran, Iran), 2 \u0026micro;L of cDNA, and 0.6 \u0026micro;L each of the forward and reverse primers (10 \u0026micro;M). The q-RT PCR protocol included one cycle at 94\u0026deg;C for 1 minute, followed by 40 cycles of denaturation at 94\u0026deg;C for 10 seconds and annealing/extension at 60\u0026deg;C for 30 seconds. The U6 primer served as the internal control.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll data are presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). The Wilcoxon test was employed to compare differences between the two data groups. For the correlation analysis of relative gene expression with clinical parameters, Spearman's rank correlation coefficient was used. All analyses were conducted using GraphPad Prism Software Version 9. A p-value of less than 0.05 was deemed statistically significant. Statistically significant differences are indicated by asterisks (* p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, ** p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, *** p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eA comparative analysis of the expression levels of miR-21, miR-146, and miR-155 genes was conducted between treatments with Etomidate and Propofol.\u003c/b\u003e The expression of miR-21 was notably downregulated with fold changes of T1\u0026thinsp;=\u0026thinsp;0.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.167 (P\u0026thinsp;=\u0026thinsp;0.026) for Etomidate and T1\u0026thinsp;=\u0026thinsp;0.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.174 (P\u0026thinsp;=\u0026thinsp;0.005) for Propofol treatments, observed both postoperatively and 24 hours following surgery, with fold changes recorded as T2\u0026thinsp;=\u0026thinsp;0.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81 (P\u0026thinsp;=\u0026thinsp;0.037), T2\u0026thinsp;=\u0026thinsp;0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 (P\u0026thinsp;=\u0026thinsp;0.036), respectively.\u003c/p\u003e \u003cp\u003eConversely, miR-146 exhibited an upregulation, with fold changes of T1\u0026thinsp;=\u0026thinsp;1.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63 (P\u0026thinsp;=\u0026thinsp;0.025) for Etomidate and T1\u0026thinsp;=\u0026thinsp;1.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43 (p\u0026thinsp;=\u0026thinsp;0.004) for Propofol. Statistical evaluations indicated significant differences in expression levels postoperatively for Etomidate and Propofol (P\u0026thinsp;=\u0026thinsp;0.025, P\u0026thinsp;=\u0026thinsp;0.004, respectively). Although no significant differences were noted at the 24-hour post-surgery for Etomidate: T2\u0026thinsp;=\u0026thinsp;1.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.488 (p\u0026thinsp;=\u0026thinsp;0.086), and But, it is induction with propofol is significant; T2\u0026thinsp;=\u0026thinsp;1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79 (P\u0026thinsp;=\u0026thinsp;0.045) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNotably, the expression levels of miR-155 did not exhibit any significant variations between the two treatment modalities: T1\u0026thinsp;=\u0026thinsp;0.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 (P\u0026thinsp;=\u0026thinsp;0.189) and T2\u0026thinsp;=\u0026thinsp;0.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35 (P\u0026thinsp;=\u0026thinsp;0.35) for Etomidate and T1\u0026thinsp;=\u0026thinsp;0.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43 (p\u0026thinsp;=\u0026thinsp;0.004), and T2\u0026thinsp;=\u0026thinsp;0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49 (P\u0026thinsp;=\u0026thinsp;0.48) for Propofol. The comparative analysis of miR-21, miR-146, and miR-155 expression is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, both in the postoperative period and 24 hours following the surgical procedure.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eThe association between the expressions of differentially expressed genes was examined by utilizing the fold change ratio for each gene to determine the correlation coefficient.\u003c/strong\u003e A negative correlation was observed between the expressions of miR-21 and miR-146 in T1 (r = -0.65; moderate; p = 0.025) and in T2 (r = -0.2; weak; p = 0.166).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe association between gene expression in patients receiving propofol and etomidate anaesthesia and their clinicopathological characteristics was examined\u003c/strong\u003e. The analysis revealed no significant correlation between the levels of differentially expressed genes and various clinicopathological factors, including sex, age, body mass index (BMI), challenges in isolation during the ICU stay, as well as SGOT and SGPT levels in the patients (Table I, Table II).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eTable I: Association between expression of the selected genes and clinicopathological characteristics of patients anesthetized with Etomidate.\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable dir=\"\" border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003emiR-155\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003emiR-146\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003emiR-21 \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003en/ percentage\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 122px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.09\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.31\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.23 \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.60 \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e58 %\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e42 %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eSex\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMale\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eFemale\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.31\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.35\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-.60\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e45-75\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eAge (Years)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.84\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.28\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.50\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.59\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 25.3-29.5\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 25.5-33.3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eBMI\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.81\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.73\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.59\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 57% (-)/ 43% (+)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 60% (-)/ 40%\u003cspan dir=\"RTL\"\u003e\u0026nbsp;(+)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003ehard to isolation from pump\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.72\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.59\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 57 (2)/28.8 (3)/14.2 (4)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e60% (2)/ 20% (3)/ 20% (4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eICU stay (x days)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.36\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 22-33\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 16-29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eSGOT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.57\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 23-51\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 20-41\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSGPT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eTable II: Association between expression of the selected genes and clinicopathological characteristics of patients anesthetized with propofol.\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable dir=\"rtl\" border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003emiR-155\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003emiR-146\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003emiR-21\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003en/ percentage\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eT2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eT2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eT2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.08\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.31\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.46\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.36\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e62%\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e38%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eSex\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMale\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eFemale\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.35\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.09\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.71\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e41-87\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.27\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.55\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.36\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.33\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 26-33\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 24.5-28\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.54\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.50\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.34\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 75% (-)/ 25% (+)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 34% (-)/ 66%\u003cspan dir=\"RTL\"\u003e\u0026nbsp;(+)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003ehard to isolation from pump\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.07\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.68\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 69% (2)/31% (3) *\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 50% (2)/ 50% (3) +\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eICU stay (x days)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.00\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.28\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.57\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.33\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.36\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 20-25\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 24-25 +\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSGOT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.00\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.31\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.63\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.55\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-0.60\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eM: 20-28\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF: 22-26 +\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSGPT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 511px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1 male patient stayed at ICU for 14 days\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1 female patient stayed at ICU for 5 days; SGOT: 83 , and SGPT: 75\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":" \u003cp\u003eEtomidate and Propofol are both agents used for general anesthesia, each exhibiting distinct effects on several parameters. These parameters encompass myocardial function, blood pressure, heart rate, and intubation, which are regarded as primary outcomes. Furthermore, myoclonic movements, along with postoperative nausea and vomiting, are classified as secondary outcomes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study aimed to assess the impact of Propofol and Etomidate on miRNA related to inflammation and neurotoxicity in blood cells among individuals undergoing these surgical interventions for the first time. It also sought to investigate the correlation of differentially expressed genes (DEGs) with various clinicopathological factors, including age, sex, body mass index (BMI), difficulties in ICU isolation, and levels of SGOT and SGPT as markers of inflammation and hepatotoxicity. Additionally, epinephrine and norepinephrine were examined as markers of inflammation and indicators of neurotoxicity.\u003c/p\u003e \u003cp\u003ePrevious studies have reported that the administration of etomidate in cirrhotic patients with sepsis results in an exceedingly high 28-day mortality rate, and an increase in ICU mortality [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, the well-known anti-inflammatory and antioxidant effects of Propofol in surgical trauma are significant [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Propofol has been shown to reduce neuroinflammation associated with surgery in mouse models, leading to a decrease in accelerated Alzheimer's neuropathology and symptoms compared to volatile anesthesia [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. It is crucial to assess the effects of Etomidate and Propofol on key molecular biomarkers.\u003c/p\u003e \u003cp\u003eThe current research focuses on the expression levels of miR-21-5p, miR-146a-5p, and miR-155. These microRNAs regulate inflammatory responses, inflammation suppression, and antidepressant responses in various diseases such as neurological disease, autoimmune disease, cancer, and infectious diseases, according to investigations [\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The downregulation of miR-21 is linked to neuronal death, and its overexpression plays a protective role in keeping neurons safe [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] while the upregulation of miR-146a is associated with the progression of Alzheimer\u0026rsquo;s disease and cognitive impairment [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, miR-155 may serve as a potential biomarker for heart failure and neuroinflammation. This evaluation will help in selecting a safer induction agent and determining suitable dosages to manage primary outcomes, as well as safeguarding patients against potential secondary outcomes.\u003c/p\u003e \u003cp\u003eWe found that: 1) Patients undergoing anesthesia induction with Propofol and Etomidate during cardiac surgery demonstrate a significant decrease in miR-21 expression after the procedure. The level of miR-21 under treatment with Propofol approximately returns to baseline within the first 24 hours post-surgery, 2) The expression of miR-146 was found to be elevated following surgery within a 24-hour period, 3) the expression levels of miR-155 were not influenced by exposure to Propofol and Etomidate, 4) The association analysis indicated a notable moderate correlation between miR-21 and miR-146a, which is introduced as inflammaging miRs by studies performed during \u0026ldquo;epigenetic revolution\" [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. 5) no correlation was identified between these differentially expressed genes and the clinicopathological characteristics. 6) Etomidate and Propofol show no significant differences in either primary or secondary clinical outcomes, 7) Based on our results regarding miR-21 and miR-146a expression, it is assumed that Propofol and Etomidate, respectively, show no preferences for the selection of anesthetic agents in enrolled patients. However, based on the variation in the genetic background of studied patients, these data can be influenced. We can conclude that more studies and monitoring of patients are needed for substantial preferences in the selection of anesthetic agents. Based on clinicopathological features, there are no substantial preferences in the selection of anesthetic agents when comparing Etomidate to Propofol.\u003c/p\u003e \u003cp\u003eIt is worth note that anti-inflammatory effect of Propofol is known and the neuroinflammation associated with surgery, leading to accelerated Alzheimer's neuropathology and symptoms, is reduced by Propofol compared with volatile anesthesia [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. We consistently noted that among our patients undergoing on cardiothoracic surgery there were no clinical complications linked to SGOT, SGPT, epinephrine, norepinephrine, intubation levels, duration of ICU stay, or ICU mortality within a seven-day timeframe after the administration of Etomidate and Propofol (Table I, II).\u003c/p\u003e \u003cp\u003eResearch highlighted the hepatotoxic effects of Propofol under hypoxic conditions in rat models. Also, it was found that Propofol protects the liver, kidney, and heart in rats with sepsis by inhibiting HMGB1 expression [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eData from \u003cem\u003ein vivo\u003c/em\u003e studies indicate that a duration of 5\u0026ndash;6 hours of Propofol exposure, which is essential for sustaining surgical anesthesia, resulted in significant neuroapoptosis in both fetal and primate models. Furthermore, a 5-hour exposure to Propofol was associated with cell death in neonatal rat hippocampal neurons. In addition, an increase in activated caspase-3 levels was observed immediately after exposure in 7-day-old rats [\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In a pioneering \u003cem\u003ein vitro\u003c/em\u003e study, Twaroski et al. (2024) revealed that even a clinically relevant dose of Propofol administered over 6 hours led to substantial cell death in neurons derived from 2-week-old human embryonic stem cells [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. They found that the downregulation of miR-21 following Propofol exposure may have contributed to neuronal cell death, potentially through the STAT3-miR-21-Sprouty 2-Akt signaling pathway [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur research indicates that patients undergoing anesthesia induction with Propofol and Etomidate during cardiac surgery demonstrate a significant decrease in miR-21 expression after the procedure. We further underline that an expression decreasing is significantly more pronounced by Propofol induction compared to Etomidate. The level of miR-21 under treatment with Propofol is returning to baseline within the first 24 hours post-surgery. The restoration of expression levels within 24 hours may contribute to alleviating potential neurotoxic effects; however, careful monitoring remains essential due to the risk of both irreversible and reversible neurotoxic adverse effects. This is particularly important as we lack data regarding the duration required for neurotoxicity associated with Propofol or Etomidate in humans, which can vary based on genetic differences. Additionally, the signaling pathways related to miR-21 warrant further investigation, and the existence of interconnected expression networks should also be considered. Inconsistent with earlier studies. Our biochemical analyses reveal that the expression of miR-21 does not correlate with factors such as sex, age, BMI, difficulties in isolation from the ICU stay, or levels of SGOT, SGPT, epinephrine, or norepinephrine.\u003c/p\u003e \u003cp\u003eConversely, the expression of miR-146a was found to be elevated following surgery. It was returning to baseline levels 24 hours after surgery when Etomidate was administered. However, the expression of miR-146 increased significantly when Propofol was administered during this time. To the best of our knowledge, this study is the first to investigate miR-146a expression in patients treated with Propofol and Etomidate after cardiac surgery. Saba et al. (2014) identified miR-146a as a crucial negative regulator of the innate immune response [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In 2020, Fan et al. emphasized that microRNA-146a acts as a significant regulator of neuroinflammation and represents a potential therapeutic target for neurological disorders, highlighting its potential as both a biomarker and a treatment target [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Furthermore, Gomes et al. (2022) demonstrated that the depletion of miR-146a in neurotoxic astrocytes from ALS patients could provide therapeutic advantages [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, Ma et al. (2021) indicated that miR-146a is instrumental in the progression of Alzheimer's disease through the miR-146a/STAT1/MYC pathway [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, miR-146a expression has been linked to cognitive dysfunction in Alzheimer's disease [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Our findings, consistent with prior data, indicate for the first time an upregulation of miR-146a expression following the administration of Propofol and Etomidate.\u003c/p\u003e \u003cp\u003eNotably, there is no observed correlation between miR-146a expression and various clinicopathological factors, including sex, age, BMI, challenges in isolation from the ICU, or levels of SGOT, SGPT, epinephrine, or norepinephrine. This lack of correlation may be attributed to the complex interconnections within the gene expression network. It is crucial to highlight that we currently lack information regarding the duration required for neurotoxicity linked to Propofol or Etomidate in humans in relation to miR-146 expression. This underscores the necessity for studies employing human stem cell-derived neurons as a model, particularly focusing on cells derived from individual patients. Additionally, there is an urgent requirement for further research into the signaling pathways related to miR-146; however, it is also important to take into account the presence of interconnected expression networks.\u003c/p\u003e \u003cp\u003eIt is noteworthy that the expression levels of miR-155 were not influenced by exposure to Propofol and Etomidate, which may further support a potential link to the absence of heart failure after the surgical procedure. Experimental findings have demonstrated that the anti-inflammatory properties of Propofol are diminished by the knockdown of miR-155 in cells treated with Lipopolysaccharide, operating through the IRF2BP2-NFAT1 pathway, as well as through the miR-155/SOCS1 mechanism in cases of acute lung injury and microglial activity, respectively [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It is crucial to emphasize that we currently lack data on the duration necessary for neurotoxicity and neuroinflammation associated with Propofol or Etomidate in humans concerning miR-155 expression. This highlights the need for investigations utilizing \u003cem\u003ein vitro\u003c/em\u003e, \u003cem\u003ein vivo\u003c/em\u003e, and particularly \u003cem\u003eex vivo\u003c/em\u003e models. Furthermore, there is an immediate necessity for additional research into the signaling pathways associated with miR-155; however, it is equally important to consider the existence of interconnected expression networks as previously mentioned.\u003c/p\u003e \u003cp\u003eThe association analysis indicated a notable moderate correlation between miR-21 and miR-146a, which is introduced as inflammaging miRs by studies performed during \u0026ldquo;epigenetic revolution\" [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Nevertheless, no correlation was identified between these differentially expressed genes and the clinicopathological characteristics.\u003c/p\u003e \u003cp\u003eIt has been noted that Etomidate affects adrenal suppression in patients suffering from sepsis and is linked to clinically significant transient hypotension when compared to other sedatives. However, this did not result in statistically significant differences in the secondary clinical outcomes [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Etomidate increases epinephrine levels by inhibiting its metabolism, which makes its use contraindicated. Nonetheless, no interactions were found between Adrenaline and Propofol. It is important to highlight that this does not rule out the possibility of potential interactions. In 2006, Niwa et al. suggested that Propofol might mitigate the increased cardiovascular response triggered by epinephrine [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Our study indicated that the use of Etomidate and Propofol does not affect adrenal function.\u003c/p\u003e \u003cp\u003eFurthermore, our investigation reveals that Etomidate and Propofol show no significant differences in either primary or secondary clinical outcomes. We have determined that there are no substantial preferences in the selection of anesthetic agents for adults be when comparing Etomidate to Propofol. Both agents affect the expression of miR-21 and miR-146, which are essential in the context of neurotoxicity and neuroinflammation related to cognitive dysfunction and the progression of Alzheimer\u0026rsquo;s disease.\u003c/p\u003e \u003cp\u003eThe notable limitation of this study may be the inadequate duration of patient monitoring. Additionally, the second limitation is that we assessed the expression of microRNAs (miRs) and certain clinical parameters as the final endpoints. These agents may have molecular effects that could impact long-term outcomes, such as elevated intracellular ion levels, including calcium, and disrupted cell signaling. The third limitation is that research involving human subjects was limited to blood cells. It is important to note that \u003cem\u003eex vivo\u003c/em\u003e models can be utilized to examine the effects of anesthesia.\u003c/p\u003e \u003cp\u003eIn conclusion, this is the first time that microRNA-21, 146 and 155 expression in the Anesthetic Propofol and Etomidate has been studied. The observed downregulation and upregulation in the blood cells of patients following exposure to Propofol and Etomidate may potentially lead to cognitive impairments and learning difficulties, as evidenced by animal studies. Ultimately, the identification of the altered expression patterns of miR-21 and miR-146 during anesthesia induced by Propofol and Etomidate could open avenues for future research focused on patient monitoring and the development of neuroprotective strategies. Therefore, we advocate for the use of microarray, RNA-seq analyses, and epigenomic studies to investigate microRNA networks, particularly with a focus on cardiac muscle or blood transcriptomes. Additional research should be conducted utilizing \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003eex vivo\u003c/em\u003e cell culture methodologies and gene knockdown techniques targeting relevant factors associated with drug responsiveness.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving humans were approved by Ethical Committee Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. (IR.AJUMS.REC.1400.103). Informed consent was obtained from all enrolled patients. The studies were conducted in accordance with the local legislation and institutional requirements (Research project number: PAIN-0003). Written informed consent for participation in this study was provided by the participants, also, written informed consent was obtained from the individuals included in this article (Supplementary data).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets presented in this article cannot be publicly shared due to privacy restrictions. Requests to access the datasets should be directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFJ and HG: conceived and designed the study, obtained funding, developed methodology, performed statistical analyses and interpretation of data, reviewed, and revised the manuscript. TS: designed the study, data analysis, bioinformatics and \u003cem\u003ein silico\u003c/em\u003e study and writing\u0026ndash;original draft. SH, NB, MB: Molecular and cellular techniques, MH: statically analysis. TS. FJ, HG, NB, MB and MH: reviewed and edited. Coauthors read and accepted the manuscript. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe grateful to the staff of Golestan hospital and all enrolled patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLu Z, Zheng H, Chen Z, et al. 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Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth. 2013;110(suppl1):i29\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson Bastin ML, Baker SN, Weant KA. Effects of etomidate on adrenal suppression: a review of intubated septic patients. Hosp Pharm. 2014;49(2):177\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiwa H, Tanimoto A, Sugimura M, Morimoto Y, Hanamoto H. Cardiovascular effects of epinephrine under sedation with nitrous oxide, propofol, or midazolam. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and En.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6047179/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6047179/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eA growing body of evidence indicates that the anesthetics Propofol and Etomidate are associated with neurotoxic effects and considerable cognitive impairment. The varying impacts of these anesthetic agents on miRNA expression have been validated. Nevertheless, the effects of these substances on the cardiovascular system and their potential side effects in humans remain inadequately understood. This study aims to examine the impact of Etomidate and Propofol anesthetics on the expression profiles of miRNA in patients who are undergoing cardiovascular surgery.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eThis research examined the expression levels of miR-21, miR-146, and miR-155 in blood cells prior to and following the administration of Etomidate and Propofol. Furthermore, the study examined the relationship between these specific microRNAs and various clinicopathological characteristics. Blood samples were obtained from 60 patients for each anesthetic agent at three time points: before surgery, immediately after surgery, and 24 hours postoperatively. Mononuclear cells were separated utilizing Ficoll reagent, RNA was extracted using Qiazol reagent, and Real-Time quantitative PCR was employed to assess expression levels. The primary outcomes measured were mortality rates in the ICU and hospital, while secondary outcomes encompassed the number of ICU- and hospital-free days observed up to seven days following surgery.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe results indicate an increase in the expression levels of miR-146, a decrease in miR-21 expression, and no change in miR-155 expression. It is worth noting that while the differences observed were statistically significant, the variations in expression levels were minor. Within 24 hours post-surgery, miR-21 expression returned to the baseline level when propofol was administered prior to the procedure. Additionally, it is important to mention that miR-146 expression decreased 24 hours after surgery with Etomidate anesthesia, although this change was not statistically significant. A significant moderate inverse correlation was discovered between the expressions of miR-21 and miR-146. Furthermore, no clinical pathological issues were observed, and there was no association between the differentially expressed genes and the clinicopathological factors.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis research highlights the impact of Etomidate and Propofol on the expression of microRNAs associated with inflammation, heart failure, neurotoxicity, cognitive dysfunction, and learning difficulties. Based on clinicopathological features, there is no discernible preference for either Propofol or Etomidate for anesthesia. With achieved results showing downregulation of miR-21 and upregulation of miR-146a, it is interesting to monitor patients over time. This underscores the importance of monitoring neurotoxicity, cognitive function, and learning capabilities following surgery.\u003c/p\u003e","manuscriptTitle":"Some miRNA signatures associated with the use of Etomidate and Propofol and their implications for cardiac surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-04 08:37:59","doi":"10.21203/rs.3.rs-6047179/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f791b50-3773-4f9e-b489-133853847a90","owner":[],"postedDate":"March 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-04T08:09:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-04 08:37:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6047179","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6047179","identity":"rs-6047179","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}