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International Journal of Medical... 2024This study aims to explore the molecular mechanisms and associated pathways of myocardial infarction (MI). We employed a variety of analytical methods, including...
This study aims to explore the molecular mechanisms and associated pathways of myocardial infarction (MI). We employed a variety of analytical methods, including Mendelian Randomization (MR) analysis, transcriptome microarray data analysis, gene function and pathway enrichment analysis, untargeted metabolomic mass spectrometry analysis, and gene-metabolite interaction network analysis. The MR analysis results revealed a significant impact of mitochondrial DNA copy number on MI and coronary artery bypass grafting. Transcriptome analysis unveiled numerous differentially expressed genes associated with myocardial ischemia, with enrichment observed in cardiac function and energy metabolism pathways. Metabolomic analysis indicated a significant downregulation of mitochondrial regulation pathways in ischemic myocardium. T500 metabolite quantification analysis identified 90 differential metabolites between MI and Sham groups, emphasizing changes in metabolites associated with energy metabolism. Gene-metabolite interaction network analysis revealed the significant roles of key regulatory molecules such as HIF1A, adenosine, TBK1, ATP, NRAS, and EIF2AK3, in the pathogenesis of myocardial ischemia. In summary, this study provides important insights into the molecular mechanisms of MI and highlights interactions at multiple molecular levels, contributing to the establishment of new theoretical foundations for the diagnosis and treatment of MI.
Topics: Myocardial Infarction; Humans; Adenosine; Energy Metabolism; Gene Regulatory Networks; Gene Expression Profiling; Mendelian Randomization Analysis; DNA, Mitochondrial; Mitochondria; Metabolomics; Transcriptome
PubMed: 38818463
DOI: 10.7150/ijms.97066 -
Scientific Reports May 2024Pulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant...
Pulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant and immune-enhancing effects, its role in PAH treatment and the underlying mechanisms remain unclear. The therapeutic effects of Cordycepin on rats with PAH were investigated using a monocrotaline (MCT)-induced rat model. The metabolic effects of Cordycepin were assessed based on the plasma metabolome. The potential mechanisms of Cordycepin in PAH treatment were investigated through transcriptome sequencing and validated in pulmonary artery smooth muscle cells (PASMC). Evaluations included hematoxylin and eosin staining for pulmonary vascular remodeling, CCK-8 assay, EDU, and TUNEL kits for cell viability, proliferation, and apoptosis, respectively, and western blot for protein expression. Cordycepin significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) in PAH rats, and mitigated pulmonary vascular remodeling. Plasma metabolomics showed that Cordycepin could reverse the metabolic disorders in the lungs of MCT-induced PAH rats, particularly impacting linoleic acid and alpha-linolenic acid metabolism pathways. Transcriptomics revealed that the P53 pathway might be the primary pathway involved, and western blot results showed that Cordycepin significantly increased P53 and P21 protein levels in lung tissues. Integrated analysis of transcriptomics and metabolomics suggested that these pathways were mainly enriched in linoleic acid metabolism and alpha-linolenic acid metabolism pathway. In vitro experiments demonstrated that Cordycepin significantly inhibited the PDGFBB (PD)-induced abnormal proliferation and migration of PASMC and promoted PD-induced apoptosis. Meanwhile, Cordycepin enhanced the expression levels of P53 and P21 proteins in PD-insulted PASMC. However, inhibitors of P53 and P21 eliminated these effects of Cordycepin. Cordycepin may activate the P53-P21 pathway to inhibit abnormal proliferation and migration of PASMC and promote apoptosis, offering a potential approach for PAH treatment.
Topics: Animals; Deoxyadenosines; Rats; Male; Apoptosis; Pulmonary Arterial Hypertension; Cell Proliferation; Transcriptome; Metabolomics; Myocytes, Smooth Muscle; Monocrotaline; Pulmonary Artery; Rats, Sprague-Dawley; Disease Models, Animal; Vascular Remodeling; Tumor Suppressor Protein p53; Linoleic Acid; Hypertrophy, Right Ventricular; Gene Expression Profiling
PubMed: 38816406
DOI: 10.1038/s41598-024-62163-3 -
Turkish Journal of Medical Sciences 2023Temporomandibular Disorders (TMD), as in the occurrence of many diseases, have been associated with oxidative stress (OS) resulting from the disruption of antioxidant...
BACKGROUND/AIM
Temporomandibular Disorders (TMD), as in the occurrence of many diseases, have been associated with oxidative stress (OS) resulting from the disruption of antioxidant mechanisms and the accumulation of reactive oxygen species in tissues. This study was designed to compare salivary and serum OS and inflammation markers of individuals with TMD and healthy subjects.
MATERIALS AND METHODS
A prospective cross-sectional study was conducted. Twenty-seven TMD patients diagnosed with disc displacement (DD) according to Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and 17 healthy subjects were enrolled in the study. Prior to any treatment, serum, and saliva samples were taken from the patients and centrifuged, and stored at -80 °C until analyzed. All samples were examined for Interleukin-6 (IL-6), Malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) concentrations.
RESULTS
There was no significant difference between the groups regarding median values of 8-OHdG, IL-6, and MDA (p > 0.05). When the relationship between serum and salivary 8-OHdG, IL-6, and MDA levels in all subjects was evaluated, there was a strong positive correlation between the levels of 8-OHdG and IL-6 in the serum (r = 0.752, p <0.001). In the study group, when the relationship between pain levels and serum and saliva 8-OHdG, IL-6, and MDA levels was assessed, a positive and strong correlation was found between the levels of 8-OHdG and IL-6 in serum.
CONCLUSION
Although the strong correlation between pain scores and serum 8-OHdG and MDA levels supports the hypothesis that inflammation and OS mechanisms may be interrelated, according to the results of the study, inflammatory and OS markers in patients with TMD were not different from healthy individuals.
Topics: Humans; Oxidative Stress; Saliva; Temporomandibular Joint Disorders; Female; Adult; Male; Cross-Sectional Studies; Biomarkers; Interleukin-6; Prospective Studies; Malondialdehyde; Inflammation; 8-Hydroxy-2'-Deoxyguanosine; Young Adult; Middle Aged
PubMed: 38813510
DOI: 10.55730/1300-0144.5737 -
Turkish Journal of Medical Sciences 2023Titanium dioxide nanoparticles are widely used in a variety of products, including sunscreens, paints, and ceramics. However, their increasing use has raised concerns...
BACKGROUND/AIM
Titanium dioxide nanoparticles are widely used in a variety of products, including sunscreens, paints, and ceramics. However, their increasing use has raised concerns about their potential health risks. Titanium dioxide nanoparticles have been shown to have the ability to enter the bloodstream and accumulate in various tissues, reaching the fetus via the placenta. The aim of this study was to investigate the cytotoxic effects of titanium dioxide nanoparticles on a human embryonic lung cell line (HEL 299/An1) and the formation of oxidative DNA damage.
MATERIALS AND METHODS
The cytotoxic effects of brookite-based titanium dioxide nanoparticles (<100 nm) were assessed using the 3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay for 24 and 48 h. Cell titanium levels were determined using inductively coupled plasma mass spectrometry. Oxidative DNA damage was assessed by measuring the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) as a biomarker.
RESULTS
Titanium dioxide nanoparticles caused dose-dependent cytotoxicity in HEL 299/An1 cells. The IC values were 25.93 μM and 0.054 μM after 24 h and 48 h of exposure, respectively. Cell titanium levels were found to be 25,967 ppb after 24 h and 210,353 ppb after 48 h (p < 0.01). 8-OHdG was detected at 32.96 ng/mL after 24 h of exposure and 17.89 ng/mL after 48 h of exposure.
CONCLUSION
In our study, it was shown that titanium nanoparticles caused dose-dependent cytotoxicity and oxidative DNA damage in human embryonic lung cells. The nanoparticles also accumulated in cells and were taken up in higher amounts after 48 h of exposure. These findings suggest that titanium dioxide nanoparticles may pose a health risk, especially for pregnant women who may not be aware of their pregnancy. Therefore, it is important to take preventive measures to reduce exposure to these nanoparticles.
Topics: Titanium; Humans; DNA Damage; Cell Line; Lung; Oxidative Stress; Nanoparticles; 8-Hydroxy-2'-Deoxyguanosine; Cell Survival; Metal Nanoparticles
PubMed: 38813501
DOI: 10.55730/1300-0144.5733 -
Journal of Biomedical Science May 2024Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy... (Review)
Review
Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems' perspective and future opportunities. We argue that targeting the body's early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O supply. Future research will investigate the potential translation to humans.
Topics: Humans; Sepsis; Adenosine; Lidocaine; Magnesium; Fluid Therapy
PubMed: 38811967
DOI: 10.1186/s12929-024-01043-4 -
Journal of the American Heart... Jun 2024Ticagrelor is a platelet P2Y receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic... (Review)
Review
Ticagrelor is a platelet P2Y receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic stroke or high-risk transient ischemic attack. Clinical trials have evaluated the efficacy and safety of ticagrelor on ischemic and bleeding outcomes for different indications and with varying treatment approaches. As a result, there is a large body of clinical evidence demonstrating different degrees of net clinical benefit compared with other platelet inhibitor drugs based on indication, patient characteristics, clinical presentation, treatment duration, and other factors. We provide a review of the major trials of ticagrelor in the context of other randomized trials of clopidogrel and prasugrel to organize the volume of available information, elevate corroborating and conflicting data, and identify potential gaps as areas for further exploration of optimal antiplatelet treatment.
Topics: Humans; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Randomized Controlled Trials as Topic; Treatment Outcome; Coronary Artery Disease; Hemorrhage
PubMed: 38804216
DOI: 10.1161/JAHA.123.031606 -
Journal of the American Heart... Jun 2024ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y receptors inhibits platelet aggregation... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study.
BACKGROUND
ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease.
METHODS AND RESULTS
We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters.
CONCLUSIONS
AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.
Topics: Humans; Male; Ticagrelor; Female; Apyrase; Platelet Aggregation; Aspirin; Platelet Aggregation Inhibitors; Middle Aged; Adult; Double-Blind Method; Dual Anti-Platelet Therapy; Drug Therapy, Combination; Young Adult; Adenosine Diphosphate; Blood Platelets; Dose-Response Relationship, Drug; Treatment Outcome; Recombinant Proteins; Purinergic P2Y Receptor Antagonists
PubMed: 38804212
DOI: 10.1161/JAHA.123.033985 -
Journal of Translational Medicine May 2024Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases....
BACKGROUND
Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (mA) is the frequent RNA modification and plays a critical role in MIRI. However, it is unclear whether lncRNA Snhg1 regulates MIRI progression and whether the lncRNA Snhg1 was modified by mA methylation.
METHODS
Mouse cardiomyocytes HL-1 cells were utilized to construct the hypoxia/reoxygenation (H/R) injury model. HL-1 cell viability was evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were quantitated utilizing flow cytometry. RNA immunoprecipitation and dual-luciferase reporter assays were applied to measure the mA methylation and the interactions between lncRNA Snhg1 and targeted miRNA or target miRNAs and its target gene. The I/R mouse model was constructed with adenovirus expressing lncRNA Snhg1. HE and TUNEL staining were used to evaluate myocardial tissue damage and apoptosis.
RESULTS
LncRNA Snhg1 was down-regulated after H/R injury, and overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization. Besides, lncRNA Snhg1 could target miR-361-5p, and miR-361-5p targeted OPA1. Overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization though the miR-361-5p/OPA1 axis. Furthermore, WTAP induced lncRNA Snhg1 mA modification in H/R-stimulated HL-1 cells. Moreover, enforced lncRNA Snhg1 repressed I/R-stimulated myocardial tissue damage and apoptosis and regulated the miR-361-5p and OPA1 levels.
CONCLUSION
WTAP-mediated mA modification of lncRNA Snhg1 regulated MIRI progression through modulating myocardial apoptosis, mitochondrial ROS production, and mitochondrial polarization via miR-361-5p/OPA1 axis, providing the evidence for lncRNA as the prospective target for alleviating MIRI progression.
Topics: Animals; RNA, Long Noncoding; MicroRNAs; Myocardial Reperfusion Injury; Mice; Apoptosis; Mitochondrial Dynamics; Myocytes, Cardiac; Cell Line; Male; Mice, Inbred C57BL; GTP Phosphohydrolases; Reactive Oxygen Species; Adenosine; Base Sequence; Methylation; Membrane Potential, Mitochondrial
PubMed: 38796415
DOI: 10.1186/s12967-024-05330-4 -
Nutrients May 2024It has been demonstrated that isoflurane-induced anesthesia can increase the blood glucose level, leading to hyperglycemia and several adverse effects. The...
It has been demonstrated that isoflurane-induced anesthesia can increase the blood glucose level, leading to hyperglycemia and several adverse effects. The administration of a mix of ketone diester (KE) and medium-chain triglyceride (MCT) oil, named KEMCT, abolished the isoflurane-anesthesia-induced increase in blood glucose level and prolonged the recovery time from isoflurane anesthesia in a male preclinical rodent model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. While most preclinical studies use exclusively male animals, our previous study on blood glucose changes in response to KEMCT administration showed that the results can be sex-dependent. Thus, in this study, we investigated female WAG/Rij rats, whether KEMCT gavage (3 g/kg/day for 7 days) can change the isoflurane (3%)-anesthesia-induced increase in blood glucose level and the recovery time from isoflurane-evoked anesthesia using the righting reflex. Moreover, KEMCT-induced ketosis may enhance both the extracellular level of adenosine and the activity of adenosine A1 receptors (A1Rs). To obtain information on the putative A1R mechanism of action, the effects of an A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; intraperitoneal/i.p. 0.2 mg/kg), on KEMCT-generated influences were also investigated. Our results show that KEMCT supplementation abolished the isoflurane-anesthesia-induced increase in blood glucose level, and this was abrogated by the co-administration of DPCPX. Nevertheless, KEMCT gavage did not change the recovery time from isoflurane-induced anesthesia. We can conclude that intragastric gavage of exogenous ketone supplements (EKSs), such as KEMCT, can abolish the isoflurane-anesthesia-induced increase in blood glucose level in both sexes likely through A1Rs in WAG/Rij rats, while recovery time was not affected in females, unlike in males. These results suggest that the administration of EKSs as an adjuvant therapy may be effective in mitigating metabolic side effects of isoflurane, such as hyperglycemia, in both sexes.
Topics: Animals; Female; Isoflurane; Blood Glucose; Rats; Ketones; Anesthetics, Inhalation; Rats, Wistar; Dietary Supplements; Triglycerides; Male; Adenosine; Anesthesia
PubMed: 38794716
DOI: 10.3390/nu16101477 -
Viruses May 2024Respiratory syncytial virus (RSV) is the most prevalent cause of acute lower respiratory infection in young children. Currently, the first RSV vaccines are approved by...
Respiratory syncytial virus (RSV) is the most prevalent cause of acute lower respiratory infection in young children. Currently, the first RSV vaccines are approved by the FDA. Recently, N6-methyladenosine (mA) RNA methylation has been implicated in the regulation of the viral life cycle and replication of many viruses, including RSV. mA methylation of RSV RNA has been demonstrated to promote replication and prevent anti-viral immune responses by the host. Whether mA is also involved in viral entry and whether mA can also affect RSV infection via different mechanisms than methylation of viral RNA is poorly understood. Here, we identify mA reader YTH domain-containing protein 1 (YTHDC1) as a novel negative regulator of RSV infection. We demonstrate that YTHDC1 abrogates RSV infection by reducing the expression of RSV entry receptor CX3C motif chemokine receptor 1 (CX3CR1) on the cell surface of lung epithelial cells. Altogether, these data reveal a novel role for mA methylation and YTHDC1 in the viral entry of RSV. These findings may contribute to the development of novel treatment options to control RSV infection.
Topics: Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Adenosine; Virus Internalization; CX3C Chemokine Receptor 1; Virus Replication; Methylation; Down-Regulation; RNA Splicing Factors; Epithelial Cells; Cell Line; A549 Cells; RNA, Viral; Host-Pathogen Interactions; Nerve Tissue Proteins
PubMed: 38793659
DOI: 10.3390/v16050778