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Background: Acid-sensing ion channels are activated during myocardial ischemia and are implicated in the mechanism of myocardial ischemia-reperfusion injury (MIRI). Acid-sensing ion channel 3 (ASIC3), the most pH-sensitive member of the ASIC family, is highly expressed in myocardial tissues. However, the role of ASIC3 in MIRI and its precise effects on the myocardial metabolome remain unclear. These unknowns might be related to the cardioprotective effects observed with APETx2 post-conditioning. Method: Rat hearts subjected to Langendorff perfusion were randomly assigned to the normal (Nor) group, ischemia/reperfusion (I/R) group, ASIC3 blockade (AP) group. Rat hearts in group AP were treated with the ASIC3-specific inhibitor APETx2 (630 nM). Molecular and morphological changes were observed to elucidate the role of ASIC3 in MIRI. Bioinformatics analyses identified differential metabolites and pathways associated with APETx2 post-conditioning. Results: APETx2 post-conditioning stabilized hemodynamics in the isolated rat heart model of MIRI. It also reduced myocardial infarct size, mitigated mitochondrial damage at the ultrastructural level, and improved markers of myocardial injury and oxidative stress. Further more, we observed that phosphatidylcholine, phosphatidylethanolamine, citric acid, cyanidin 5-O-beta-D-glucoside, and L-aspartic acid decreased after MIRI. The levels of these metabolites were partially restored by APETx2 post-conditioning. These metabolites are primarily involved in autophagy and endogenous cannabinoid signaling pathways. Conclusion: ASIC3 is potentially a key player in MIRI. APETx2 post-conditioning may improve MIRI through specific metabolic changes. This study provides valuable data for future research on the metabolic mechanisms underlying the effects of APETx2 post-conditioning in MIRI. [ABSTRACT FROM AUTHOR]

Abstract Objective To screen Myocardial ischemia–reperfusion Injury in mice. adenosine monophate-activatedprotein kinase (AMPK) -related differentially expressed circularRNA (circRNA) in MIRI model, Ampk-related circRNA network was drawn to provide possible ideas for the prevention and treatment of MIRI. Methods The mouse MIRI model was constructed by ligation of the left anterior descending artery. After the model was successfully established, the related indicators of cardiac function were detected, and high-throughput sequencing was performed on the myocardial tissue of the mice. Results MIRI model was successfully constructed, and two AMPK related differentially expressed loops (novel_circ_043550 and novel_circ_035243) were screened out. A circRNA-miRNA-mRNA network consisting of 2 circRNA, 28 microRNA(miRNA) and 229 messengerRNA (mRNA) was constructed. Conclusions This study reveals the differential expression of several AMPK-related circRNAs in MIRI in mice, and the AMPK-related circRNA regulatory network is constructed, suggesting that AMPK-related circRNA may have potential clinical application prospects as a potential molecular marker and therapeutic target for MIRI.

Abstract Aims This study aims to explore the molecular mechanism of circular RNAs' (circRNAs) potential involvement in myocardial ischaemia–reperfusion injury (MIRI). Methods and results Differently expressed genes in myocardial infarction (MI) were identified by screening the GEO database. Serum was collected from MI patients and healthy volunteers (n = 5 for each group). AC16 cells were cultured and exposed to hypoxia/reperfusion (H/R) treatment for the cell experiments. Then candidate genes were validated in human serum and the H/R model. Quantitative real‐time PCR and western blot were used to detect expression of key molecules such as circDGKZ, miR‐345‐5p, and Toll‐like receptor 4 (TLR4), as well as pyroptosis markers such as NOD‐like receptor thermal protein domain‐associated protein 3 (NLRP3), ASC, C‐caspase1, interleukin (IL)‐1β, and IL‐18. CircDGKZ was positively correlated in human serum (P

Aims: This study aims to explore the molecular mechanism of circular RNAs' (circRNAs) potential involvement in myocardial ischaemia–reperfusion injury (MIRI). Methods and results: Differently expressed genes in myocardial infarction (MI) were identified by screening the GEO database. Serum was collected from MI patients and healthy volunteers (n = 5 for each group). AC16 cells were cultured and exposed to hypoxia/reperfusion (H/R) treatment for the cell experiments. Then candidate genes were validated in human serum and the H/R model. Quantitative real‐time PCR and western blot were used to detect expression of key molecules such as circDGKZ, miR‐345‐5p, and Toll‐like receptor 4 (TLR4), as well as pyroptosis markers such as NOD‐like receptor thermal protein domain‐associated protein 3 (NLRP3), ASC, C‐caspase1, interleukin (IL)‐1β, and IL‐18. CircDGKZ was positively correlated in human serum (P < 0.05) and in AC16 cells (P < 0.01). Knockdown of circDGKZ inhibited cardiomyocyte pyroptosis and the TLR4/nuclear factor kappa B (NF‐κB) signalling pathway (all P < 0.05). A luciferase assay was used to detect the molecule interaction. MiR‐345‐5p was regulated by circDGKZ and regulated TLR4 in cardiomyocytes both through direct interaction (P < 0.01). The stability and distribution of circRNA or linear RNA were examined by subcellular localization and RNA decay assays. CircDGKZ was stably expressed in cardiomyocytes and mainly distributed in the cytoplasm (P < 0.01). Knockdown of circDGKZ also promoted the degradation of NLRP3 by inducing autophagy (P < 0.05). MIRI rat models were constructed (n = 5 for each group), and the cellular results were further confirmed in rat models (P < 0.05). Conclusions: Knockdown of circDGKZ interrupted pyroptosis and induced autophagy of cardiomyocytes via regulating miR‐345‐5p/TLR4/NF‐κB. [ABSTRACT FROM AUTHOR]

BackgroundAcid-sensing ion channels are activated during myocardial ischemia and are implicated in the mechanism of myocardial ischemia-reperfusion injury (MIRI). Acid-sensing ion channel 3 (ASIC3), the most pH-sensitive member of the ASIC family, is highly expressed in myocardial tissues. However, the role of ASIC3 in MIRI and its precise effects on the myocardial metabolome remain unclear. These unknowns might be related to the cardioprotective effects observed with APETx2 post-conditioning.MethodRat hearts subjected to Langendorff perfusion were randomly assigned to the normal (Nor) group, ischemia/reperfusion (I/R) group, ASIC3 blockade (AP) group. Rat hearts in group AP were treated with the ASIC3-specific inhibitor APETx2 (630 nM). Molecular and morphological changes were observed to elucidate the role of ASIC3 in MIRI. Bioinformatics analyses identified differential metabolites and pathways associated with APETx2 post-conditioning.ResultsAPETx2 post-conditioning stabilized hemodynamics in the isolated rat heart model of MIRI. It also reduced myocardial infarct size, mitigated mitochondrial damage at the ultrastructural level, and improved markers of myocardial injury and oxidative stress. Further more, we observed that phosphatidylcholine, phosphatidylethanolamine, citric acid, cyanidin 5-O-beta-D-glucoside, and L-aspartic acid decreased after MIRI. The levels of these metabolites were partially restored by APETx2 post-conditioning. These metabolites are primarily involved in autophagy and endogenous cannabinoid signaling pathways.ConclusionASIC3 is potentially a key player in MIRI. APETx2 post-conditioning may improve MIRI through specific metabolic changes. This study provides valuable data for future research on the metabolic mechanisms underlying the effects of APETx2 post-conditioning in MIRI.

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is defined as the restoration of blood flow to the myocardium after a brief interruption of blood supply, causing more severe damage to the ischemic myocardium. However, currently, reperfusion therapy is the preferred therapy for ischemic cardiomyopathy, which undoubtedly causes MIRI, and thus it has become a challenging issue affecting the prognosis of coronary artery disease. Methods A search was conducted in the Web of Science Core Collection database for papers relevant to MIRI therapy published between 1 January 2000 and 1 October 2023. Bibliometric analyses were performed using VOSviewer and CiteSpace to elucidate the progress and hotspots. Results 3304 papers from 64 countries, 2134 research institutions and 13,228 authors were enrolled in the study. Of these, China contributed the most papers and had the biggest impact, while the United States had the most extensive partnership. The Fourth Military Medical University was the primary research institution. The most valuable authors include Chattipakorn, Nipon, Chattipakorn, Siriporn c, Yang, Jian and Yang, Yang. Conclusion Over the past 20 years, research on MIRI therapies has made significant strides. Further studies are necessary to explore the interactions between various therapeutic options. Future investigations will emphasize nanocarriers, cardiac regeneration, and stem cell therapies. Our study identifies MIRI research hotspots from a bibliometric perspective, forecasts future trends, and offers fresh insights into MIRI therapy research.

Myocardial ischemia causes extensive damage, further exacerbated by reperfusion, a phenomenon called myocardial ischemia/reperfusion injury (MIRI). Nowadays, the pathological mechanisms of MIRI have received extensive attention. Oxidative stress, multiple programmed cell deaths, inflammation and others are all essential pathological mechanisms contributing to MIRI. Mitochondria are the energy supply centers of cells. Numerous studies have found that abnormal mitochondrial function is an essential ''culprit'' of MIRI, and mitophagy mediated by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin signaling pathway is an integral part of maintaining mitochondrial function. Therefore, exploring the association between the PINK1/Parkin signaling pathway-mediated mitophagy and MIRI is crucial. This review will mainly summarize the crucial role of the PINK1/Parkin signaling pathway-mediated mitophagy in MIR-induced several pathological mechanisms and various potential interventions that affect the PINK1/Parkin signaling pathway-mediated mitophagy, thus ameliorating MIRI.

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) 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 m6A 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 m6A 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 m6A 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 m6A 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.

Background: Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) 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 m6A 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 m6A 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 m6A 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 m6A 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. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury (MIRI) is a complex process that occurs when blood flow is restored after myocardium infarction (MI) with exacerbated tissue damage. Macrophages, essential cell type of the immune response, play an important role in MIRI. Macrophage subpopulations, namely M1 and M2, are distinguished by distinct phenotypes and functions. In MIRI, macrophages infiltrate in infarcted area, shaping the inflammatory response and influencing tissue healing. Resident cardiac macrophages interact with monocyte-derived macrophages in MIRI, and influence injury progression. Key factors including chemokines, cytokines, and toll-like receptors modulate macrophage behavior in MIRI. This review aims to address recent findings on the classification and the roles of macrophages in the myocardium, spanning from MI to subsequent MIRI, and highlights various signaling pathways implicated in macrophage polarization underlining the complexity of MIRI. This article will shed light on developing advanced therapeutic strategies for MIRI management. • Modulation of macrophage polarization as a potential target for treating Myocardial Ischemia Reperfusion Injury (MIRI). • Summary for cell types of macrophages and their function. • Localization & phenotypes of macrophages in myocardial tissue. • Conclusion for recent researches of the potential mechanism of macrophages during myocardial infarction (MI) & MIRI. [ABSTRACT FROM AUTHOR]

Abstract Background Myocardial ischemia reperfusion injury (MIRI), the tissue damage which is caused by the returning of blood supply to tissue after a period of ischemia, greatly reduces the therapeutic effect of treatment of myocardial infarction. But the underlying functional mechanisms of MIRI are still unclear. Methods We constructed mouse models of MIRI, extracted injured and healthy myocardial tissues, and performed transcriptome sequencing experiments (RNA-seq) to systematically investigate the dysregulated transcriptome of MIRI, especially the alternative splicing (AS) regulation and RNA binding proteins (RBPs). Selected RBPs and MIRI-associated AS events were then validated by RT-qPCR experiments. Results The differentially expressed gene (DEG) analyses indicated that transcriptome profiles were changed by MIRI and that DEGs’ enriched functions were consistent with MIRI’s dysregulated pathways. Furthermore, the AS profile was synergistically regulated and showed clear differences between the mouse model and the healthy samples. The exon skipping events significantly increased in MIRI model samples, while the opposite cassette exon events significantly decreased. According to the functional analysis, regulated alternative splicing genes (RASGs) were enriched in protein transport, cell division /cell cycle, RNA splicing, and endocytosis pathways, which were associated with the development of MIRI. Meanwhile, 493 differentially expressed RBPs (DE RBPs) were detected, most of which were correlated with the changed ratios of AS events. In addition, nine DE RBP genes were validated, including Eif5, Pdia6, Tagln2, Vasp, Zfp36l2, Grsf1, Idh2, Ndrg2, and Uqcrc1. These nine DE RBPs were correlated with RASGs enriched in translation process, cell growth and division, and endocytosis pathways, highly consistent with the functions of all RASGs. Finally, we validated the AS ratio changes of five regulated alternative splicing events (RASEs) derived from important regulatory genes, including Mtmr3, Cdc42, Cd47, Fbln2, Vegfa, and Fhl2. Conclusion Our study emphasized the critical roles of the dysregulated AS profiles in MIRI development, investigated the potential functions of MIRI-associated RASGs, and identified regulatory RBPs involved in AS regulation. We propose that the identified RASEs and RBPs could serve as important regulators and potential therapeutic targets in MIRI treatment in the future.

Background: Myocardial ischemia reperfusion injury (MIRI), the tissue damage which is caused by the returning of blood supply to tissue after a period of ischemia, greatly reduces the therapeutic effect of treatment of myocardial infarction. But the underlying functional mechanisms of MIRI are still unclear. Methods: We constructed mouse models of MIRI, extracted injured and healthy myocardial tissues, and performed transcriptome sequencing experiments (RNA-seq) to systematically investigate the dysregulated transcriptome of MIRI, especially the alternative splicing (AS) regulation and RNA binding proteins (RBPs). Selected RBPs and MIRI-associated AS events were then validated by RT-qPCR experiments. Results: The differentially expressed gene (DEG) analyses indicated that transcriptome profiles were changed by MIRI and that DEGs' enriched functions were consistent with MIRI's dysregulated pathways. Furthermore, the AS profile was synergistically regulated and showed clear differences between the mouse model and the healthy samples. The exon skipping events significantly increased in MIRI model samples, while the opposite cassette exon events significantly decreased. According to the functional analysis, regulated alternative splicing genes (RASGs) were enriched in protein transport, cell division /cell cycle, RNA splicing, and endocytosis pathways, which were associated with the development of MIRI. Meanwhile, 493 differentially expressed RBPs (DE RBPs) were detected, most of which were correlated with the changed ratios of AS events. In addition, nine DE RBP genes were validated, including Eif5, Pdia6, Tagln2, Vasp, Zfp36l2, Grsf1, Idh2, Ndrg2, and Uqcrc1. These nine DE RBPs were correlated with RASGs enriched in translation process, cell growth and division, and endocytosis pathways, highly consistent with the functions of all RASGs. Finally, we validated the AS ratio changes of five regulated alternative splicing events (RASEs) derived from important regulatory genes, including Mtmr3, Cdc42, Cd47, Fbln2, Vegfa, and Fhl2. Conclusion: Our study emphasized the critical roles of the dysregulated AS profiles in MIRI development, investigated the potential functions of MIRI-associated RASGs, and identified regulatory RBPs involved in AS regulation. We propose that the identified RASEs and RBPs could serve as important regulators and potential therapeutic targets in MIRI treatment in the future. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion injury (MIRI) is a prevalent condition associated with numerous critical clinical conditions. miR‐322 has been implicated in MIRI through poorly understood mechanisms. Our preliminary analysis indicated potential interaction of CREB‐binding protein (CBP), a transcriptional coactivator and acetyltransferase, with HIF‐1α/β‐catenin, which might regulate miR‐322 expression. We, therefore, hypothesized that CBP/HIF‐1α/β‐catenin/miR‐322 axis might play a role in MIRI. Rat cardiomyocytes subjected to oxygen‐glucose deprivation /reperfusion (OGD/R) and Langendorff perfused heart model were used to model MIRI in vitro and in vivo, respectively. We used various techniques such as CCK‐8 assay, transferase dUTP nick end labeling staining, western blotting, RT‐qPCR, chromatin immunoprecipitation (ChIP), dual‐luciferase assay, co‐immunoprecipitation (Co‐IP), hematoxylin and eosin staining, and TTC staining to assess cell viability, apoptosis, and the levels of CBP, HIF‐1α, β‐catenin, miR‐322, and acetylation. Our results indicate that OGD/R in cardiomyocytes decreased CBP/HIF‐1α/β‐catenin/miR‐322 expression, increased cell apoptosis and cytokines, and reduced cell viability. However, overexpression of CBP or miR‐322 suppressed OGD/R‐induced cell injury, while knockdown of HIF‐1α/β‐catenin further exacerbated the damage. HIF‐1α/β‐catenin bound to miR‐322 promoter to promote its expression, while CBP acetylated HIF‐1α/β‐catenin for stabilization. Overexpression of CBP attenuated MIRI in rats by acetylating HIF‐1α/β‐catenin to stabilize their expression, resulting in stronger binding of HIF‐1α/β‐catenin with the miR‐322 promoter and subsequent increased miR‐322 levels. Therefore, activating CBP/HIF‐1α/β‐catenin/miR‐322 signaling may be a potential approach to treat MIRI. [ABSTRACT FROM AUTHOR]

Abstract Aims Myocardial ischaemia/reperfusion injury (MIRI) is a major cause of heart failure after myocardial infarction. Berberine (BBR) presents anti‐inflammatory and immunosuppressive properties in many diseases. Our research looked into the therapeutic effects and mechanism of BBR in MIRI. Methods and results MIRI animal and cell models were established. The mRNA and protein expressions were assessed using reverse transcription and quantitative real‐time polymerase chain reaction and western blot. The haemodynamic parameters (left ventricular ejection fraction and left ventricular ejection fraction) were detected by echocardiography. The myocardial infarct size and myocardium lesion were assessed by triphenyltetrazolium chloride and haematoxylin–eosin staining. The levels of injury factors were determined by ELISA. Terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling staining was performed to analyse cell apoptosis. Dual luciferase reporter gene and RNA immunoprecipitation assays were carried out to verify the interaction between miR‐340‐5p and HMGB1. BBR administration could improve the haemodynamic parameters and infarct size in MIRI rats (all P

Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski's rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study. [ABSTRACT FROM AUTHOR]

Aims: Myocardial ischaemia/reperfusion injury (MIRI) is a major cause of heart failure after myocardial infarction. Berberine (BBR) presents anti‐inflammatory and immunosuppressive properties in many diseases. Our research looked into the therapeutic effects and mechanism of BBR in MIRI. Methods and results: MIRI animal and cell models were established. The mRNA and protein expressions were assessed using reverse transcription and quantitative real‐time polymerase chain reaction and western blot. The haemodynamic parameters (left ventricular ejection fraction and left ventricular ejection fraction) were detected by echocardiography. The myocardial infarct size and myocardium lesion were assessed by triphenyltetrazolium chloride and haematoxylin–eosin staining. The levels of injury factors were determined by ELISA. Terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling staining was performed to analyse cell apoptosis. Dual luciferase reporter gene and RNA immunoprecipitation assays were carried out to verify the interaction between miR‐340‐5p and HMGB1. BBR administration could improve the haemodynamic parameters and infarct size in MIRI rats (all P < 0.05). In MIRI rat model, BBR reduced cardiomyocyte apoptosis and inflammation (all P < 0.05). BBR could promote miR‐340‐5p expression (0.64 ± 0.21, P < 0.05), which is lowly expressed in MIRI group (0.24 ± 0.10, P < 0.01) in compare with the sham group (0.99 ± 0.01). MiR‐340‐5p knockdown abolished the protective effects of BBR on H/R‐treated cardiomyocytes (all P < 0.05). BBR suppressed the HMGB1/TLR4/NF‐κB pathway activation in MIRI. HMGB1 functioned as the target of miR‐340‐5p, and its silencing reversed the effect of miR‐340‐5p inhibitor on BBR‐treated MIRI. Conclusions: In MIRI, BBR repressed HMGB1‐mediated TLR4/NF‐κB signalling pathway through miR‐340‐5p to suppress cardiomyocyte apoptosis and inflammation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Stachyose, a naturally occurring oligosaccharide, regulates GPX4 and NLRP3. • Stachyose has a significant effect in alleviating myocardial ischemia–reperfusion injury. • Stachyose modulates the ferroptotic pathway in cardiomyocytes. • Stachyose inhibits the pyroptotic pathway in macrophages. Myocardial ischemia–reperfusion injury (MIRI) is a complex pathological process that results from the restoration of blood flow to ischemic myocardium, leading to a series of detrimental effects including oxidative stress and inflammation. Stachyose, a naturally occurring oligosaccharide found in traditional Chinese medicinal herbs, has been suggested to possess therapeutic properties against various pathological conditions. However, its impact on MIRI and the underlying mechanisms have not been fully elucidated. In this study, we aimed to investigate the therapeutic effects of stachyose on MIRI and to uncover the molecular mechanisms involved. Using both in vivo and in vitro models of MIRI, we evaluated the effects of stachyose on cardiac function and cell death pathways. Our results indicate that stachyose significantly improves cardiac function and reduces infarct size in MIRI mice. Mechanistically, stachyose modulates the ferroptotic pathway in cardiomyocytes by upregulating the expression of glutathione peroxidase 4 (GPX4) and reducing lipid peroxides and iron levels. Additionally, stachyose inhibits the pyroptotic pathway in macrophages by downregulating the expression of NLRP3, gasdermin D (GSMD-N), and cleaved-caspase-1, leading to decreased levels of proinflammatory cytokines interleukin (IL)-1β and IL-18. This study demonstrates that stachyose exerts a protective effect against MIRI by targeting both ferroptosis and pyroptosis pathways, suggesting its potential as a novel therapeutic agent for the treatment of MIRI. Further research is warranted to explore the detailed mechanisms and therapeutic potential of stachyose in clinical settings. [ABSTRACT FROM AUTHOR]

Resveratrol is a natural polyphenol found in various plants. It has been widely studied on cardiovascular disorders. It is known that resveratrol can activate Sirtuin proteins and participate in cellular energy metabolism through a Sirtuin-dependent pathway. Here, we hypothesized that resveratrol may protect against myocardial ischemia/reperfusion injury (MIRI) through the target of Sirt1/Sirt3 on mitochondrial dynamics, cardiac autophagy, bioenergetics and oxidative damage in hypoxia/reoxygenation (H/R)-induced neonatal rat cardiomyocytes. We observed that resveratrol could activate the Sirt1/Sirt3-FoxO pathway on myocardial mitochondria in H/R cardiomyocytes. Subsequently, we found that resveratrol repaired the fission–fusion balance, autophagic flux and mitochondrial biosynthesis compared by H/R group. These changes were followed by increased functional mitochondrial number, mitochondrial bioenergetics and a better mitochondrial antioxidant enzyme system. Meanwhile, these effects were antagonized by co-treatment with Selisistat (Ex527), a Sirtuin inhibitor. Together, our findings uncover the potential contribution of resveratrol in reestablishing a mitochondrial quality control network with Parkin, Mfn2 and PGC-1α as the key nodes. [ABSTRACT FROM AUTHOR]

Chinese dragon's blood , the red resin of Dracaena cochinchinensis (Lour.) S. C. Chen., is widely used to treat cardiovascular and cerebrovascular diseases in China. Longxuetongluo Capsule (LTC) is a total phenolic compound extracted from Chinese dragon's blood , currently used in treating ischemic stroke. Myocardial injury can be aggravated after reperfusion of ischemic myocardium, which is called myocardial ischemia-reperfusion injury (MIRI), and the mechanism of MIRI is complex. However, the exact effect and mechanism of LTC on MIRI are still unclear. We explore the effect of LTC on alleviating MIRI based on mitochondrial dysfunction and oxidative stress. To explore the cardioprotective mechanism of LTC against MIRI. A rat MIRI model was constructed through ligation of the left anterior descending coronary artery, and LTC was given continuously for 28 days before surgery. The H9c2 cardiomyocyte injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R), and LTC was given 24 h before OGD. Myocardial ischemia areas were detected with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cardiac histopathological changes were detected with hematoxylin-eosin (HE) staining. And biochemical indexes were detected with serum biochemical kit. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining and flow cytometry were used to detect apoptosis. Fluorescent probes were used to observe reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), Ca2+and other indexes. MitoTracker staining and immunofluorescence were used to observe the morphology of mitochondria and translocation of dynamin-related protein 1 (Drp1). Finally, immunohistochemistry and Western blotting were used to examine the expression of proteins related to apoptosis, mitochondrial fission and fusion and oxidative stress. LTC could ameliorate cardiac pathological changes, decrease myocardial infarct area and the content or level of relevant serum cardiac enzymes, indicating that LTC could alleviate MIRI. Meanwhile, LTC could inhibit cardiomyocyte apoptosis via regulating apoptosis-related protein expression, and it could restore mitochondrial morphology, maintain ΔΨm, inhibit mitochondrial ROS generation and Ca2+ accumulation, increase the expression of mitochondrial fusion protein 2 (Mfn2), decrease the level of phosphorylation dynamin-related protein 1 (p-Drp1), and regulate ATP synthesis, thereby significantly ameliorating mitochondrial dysfunction. Moreover, LTC significantly reduced the expression of NADPH oxidase 2 (NOX2), NADPH oxidase 4 (NOX4) and neutrophil cytosolic factor 2 (NOXA2/p67phox), and reduced ROS production. The study demonstrated that LTC could inhibit MIRI induced cardiomyocyte apoptosis by inhibiting ROS generation and mitochondrial dysfunction, and these fundings suggested that LTC can be used to alleviate MIRI, which provides a potential therapeutic approach for future treatment of MIRI. [ABSTRACT FROM AUTHOR]

Objective and design: We aim to explore the molecular mechanism of myocardial ischemia–reperfusion injury (MIRI). Methods: The H9C2 cells were cultured under hypoxia/reoxygenation (H/R) condition to induce myocardial injury in vitro. The expression of miR-451-3p and MAP1LC3B was detected by RT-qPCR. Dual-luciferase reporter assay and RNA pull-down assay were performed to examine the relationship between microRNA (miR)-451-3p and MAP1LC3B. CCK8 was used to test cell viability. The level of LDH and CK was evaluated via ELISA. Immunofluorescence assay and flow cytometry were applied to detect autophagy and apoptosis, respectively. Autophagy-related protein expressions were determined by western blotting. Furthermore, an in vivo rat model of MIRI was established by subjection to 30 min ischemia and subsequently 24 h reperfusion for validation of the role of miR-451-3p in regulating MIRI in vivo. Results: miR-451-3p was down-regulated in MIRI, and miR-451-3p mimics transfection alleviated autophagy and apoptosis induced by MIRI. miR-451-3p could target MAP1LC3B directly. Co-transfection miR-451-3p mimics and pcDNA 3.1 MAP1LC3B curbed the protected effects of miR-451-3p mimics on MIRI. Conclusions: miR-451-3p played a protective role in MIRI via inhibiting MAP1LC3B-mediated autophagy, which may provide new molecular targets for the treatment of MIRI and further improves the clinical outcomes of heart diseases. [ABSTRACT FROM AUTHOR]

The onshore Baram Delta, located in NW Sarawak is the birthplace of petroleum production in Malaysia. The Miri oilfield was first discovered in 1910 and subsequently abandoned in 1972 with intermittent exploration activities in the late 1980's to early 1990's. To rejuvenate exploration interest and to identify remaining hydrocarbon potential of the study area, in 2009-2010 JX Nippon acquired gravity, then regional 2D seismic data, followed-by exploration well drilling from 2011-2014. This paper discusses the social-environmental impacts and concerns associated with these petroleum exploration activities, from acquisition of seismic where explosives and vibroseis were used as a source of propagating signals, to exploration drilling with petroleum chemicals such as water-based muds used to facilitate the drilling operations. Overall, the inquiry addresses operational challenges, security of explosive storage and concern for handling explosives in the field, the social-environmental impacts of seismic acquisition operations, as well as removal of drilling fluid chemicals and disposal of contaminated cuttings. Containment procedures and mitigation measures undertaken to alleviate these social-environmental impacts are discussed according to the guidelines and regulatory requirements provided by the Environmental Impact Assessment (EIA), in conjunction with PETRONAS Procedures and Guidelines for Upstream Activities (PPGUA) and the company's Health, Safety and Environment (HSE) Management System. In the final analysis, significant environmental and social challenges were certainly encountered while planning and conducting petroleum exploration activities in the study area. These challenges include problems related to topographic variabilities, permitting issues, compensations for affected lands and cash crops; layout constraints, drilling operations, well control measures for blowout prevention, traffic controls, potential damage to infra-structures, explosive and equipment transportation. However, with proper planning, effective communication with the local authorities, and awareness sessions conducted for the affected parties and stakeholders; together with the support of the local communities the operations have not only managed to mitigate these social and environmental concerns, the exploration activities also provided economic benefits such as hotel accommodation, logistics and transportation demands for local businesses, and short-term employment opportunities for the local people. Ultimately, the operations successfully acquired nearly 900-line km of seismic across many villages, longhouses, and in the city areas, with four exploration wells were drilled in the exploration block. We are glad to report that both seismic and drilling operations were conducted successfully and safely with minimal interruptions to people and environment, without untoward incidents or spills. With the mitigation measures in place, there were no damages other than land access, which were remediated, where incurred. [ABSTRACT FROM AUTHOR]

This article aimed to identify how many are the forms of consumption of acai berry and how important is the fruit in Amazonian contexts, such as the Igarapé-Miri City (PA), by the vision of the city fair. This city was chosen as a research local, because it is a locality where açai consumption is still seen as traditional and for the reason that it is considered the “Açaí World Capital”. The methodological pathway built to reach the proposed goal was established from a qualitative approach, with bibliographical, documentary and field research. From a procedural and methodological point of view, data collection instruments were used, followed by of direct observations in the Igarapé-Miri Market and Trade Complex, photographic records, informal conversations and interviews with market participants and açaí consumers. The results obtained allowed a understanding that the açaí in this city transpasses the sine qua non role of food for the human living, comprising, in fact, a cultural element of the daily life of the inhabitants of that city. It is present and represented by / in multiple and different ways, it has multifaceted functions and forms of consumption still considered traditional.

In this work, two Cu(II)-containing coordination polymers, namely, {[Cu2(L)2(dpyb)(H2O)4]·6H2O}n (1) and {[Cu2(L)2(dpyb)](CH3CN)2}n (2) have been hydrothermally synthesized based on a substituted thiophene carboxylic acid 3,3′-(thiophene-2,5-diyl)dibenzoic acid (H2L) and auxiliary N-donor co-ligand 1,4-di(pyridin-4-yl)benzene (dpyb). Furthermore, the protective effect of compounds 1 and 2 on myocardial ischemia-reperfusion injury (MIRI) was evaluated and the specific was explored. The real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed the down-regulated relative expression of the nf-κb and mapk genes after compound treatment. The enzyme-linked immunosorbent assay (ELISA) suggested the inhibitory of the compound on inflammatory cytokines IL1-β and TNF-α releasing. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion injury (MIRI) is a clinically familiar disease, which possesses a great negative impact on human health. But, the effective treatment is still absent. MicroRNAs (miRNAs) have been testified to play a momentous role in MIRI. The purpose of the study aimed to probe the functions of miR‐132 in oxygen and glucose deprivation (OGD)‐evoked injury in H9c2 cells. miR‐132 expression in H9c2 cells accompanied by OGD disposition was evaluated via real‐time quantitative polymerase chain reaction. After miR‐132 mimic and inhibitor transfections, the impacts of miR‐132 on OGD‐affected H9c2 cell viability, apoptosis, cell cycle, and the interrelated factors were appraised by exploiting cell counting kit‐8, flow cytometry, and western blot analysis. FOXO3A expression was estimated in above‐transfected cells, meanwhile, the correlation between miR‐132 and FOXO3A was probed by dual‐luciferase report assay. Ultimately, above mentioned cell processes were reassessed in H9c2 cells after preprocessing OGD administration and transfection with si‐FOXO3A and si‐NC plasmids. We got that OGD disposition obviously enhanced miR‐132 expression in H9c2 cells. Overexpressed miR‐132 evidently reversed OGD‐evoked cell viability repression and apoptosis induction in H9c2 cells. In addition, overexpressed miR‐132 mitigated OGD‐evoked G0/G1 cell arrest by mediating p21, p27, and cyclin D1 expression. Repression of FOXO3A was observed in miR‐132 mimic‐transfected cells, which was also predicated as a direct gene of miR‐132. We discovered that silenced FOXO3A alleviated OGD‐evoked cell injury in H9c2 cells via facilitating cell viability, hindering apoptosis and restraining cell arrest at G0/G1 phase. In conclusion, these investigations corroborated that miR‐132 exhibited the protective impacts on H9c2 cells against OGD‐evoked injury via targeting FOXO3A. [ABSTRACT FROM AUTHOR]

Myocardial ischaemia reperfusion injury (MIRI) is considered the primary cause of death in patients with cardiovascular diseases. Recently, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been found to be involved in the pathogenesis of MIRI. However, whether lncRNA ROR and miR-124-3p play roles in MIRI and the underlying mechanism remain undetermined. HCMs were exposed to hypoxic conditions for 2 h followed by re-oxygenation (H/R) treatment. Expression of miR-124-3p and lncRNA ROR in HCMs was measured by qRT-PCR. TRAF6 expression was evaluated by qRT-PCR and western blotting. ELISA and qRT-PCR were conducted to assess the production of TNF-α, IL-6, and IL-1β. The interaction between miR-124-3p and TRAF6, as well as between miR-124-3p and lncRNA ROR, was verified by dual-luciferase reporter assay. Cell apoptosis was detected by flow cytometry analysis. Our data revealed that miR-124-3p was significantly downregulated, while TRAF6 and lncRNA ROR were upregulated in both MIRI rat model and H/R treated HCMs. Overexpression of miR-124-3p reversed the H/R-induced cell apoptosis and upregulation of TNF-α, IL-6, and IL-1β. Mechanistically, miR-124-3p bound and negatively regulated TRAF6 expression in HCMs. Moreover, TRAF6 overexpression significantly blocked the effects of miR-124-3p mimics on cell apoptosis and inflammatory response of HCMs, which involved the NF-κB pathway. Further analysis showed that lncRNA ROR sponged and negatively regulated miR-124-3p in HCMs. Overexpression of IL-1β was demonstrated to promote H/R induced cell apoptosis in HCMs. In addition, overexpression of ROR further enhanced the H/R-induced inflammation and cell apoptosis through its action on miR-124-3p. The lncRNA ROR/miR-124-3p/TRAF6 axis regulated the H/R-induced cell apoptosis and inflammatory response of HCMs. [ABSTRACT FROM AUTHOR]

Background: Alcohol consumption in the under‐aged is one of the main concerns regarding Malaysian adolescents. There is no previous study on problematic alcohol use (PAU) in adolescents in Sarawak. The aim of this study was to determine the prevalence of PAU, its associated variables and its relationship with depression. Methods: This was a cross‐sectional study. A total of 327 secondary school students completed the Alcohol Use Disorder Identification Test and Children's Depression Inventory, and a sociodemographic questionnaire. Binary and multivariable logistic regression were used to examine the relationship between the different variables. Results: A total of 42.2% of adolescents had PAU. Urban adolescents had a higher prevalence compared with rural adolescents (OR, 1.612; 95% CI: 1.036–2.508 P = 0.034). Female adolescents (56.8%) and Bumiputera Sarawak adolescents (76.8%) comprised a large proportion of the respondents with PAU. Cultural norm (78.3%) and curiosity (68.1%) were the two main reasons for PAU. Only family history of alcohol use (OR, 2.273; 95% CI: 1.013–5.107; P = 0.047), ever consumed alcohol (OR, 57.585; 95% CI: 21.885–151.525; P < 0.001) and ever consumed beer (OR, 2.564; 95% CI: 1.032–6.372; P = 0.043) were significantly associated with PAU. The prevalence of depression was 21.4%. A significant relationship between PAU and depression was seen (OR, 2.557; 95% CI: 1.479–4.420; P = 0.001). Conclusion: There is a high prevalence of PAU in adolescents in Miri, Malaysia. More effort is needed to implement policies for this vulnerable group, with collaboration between agencies to ensure their mental and physical wellbeing and prevent a negative impact later. Clinicians should be more vigilant in detecting depression in adolescents with PAU to enable early intervention. [ABSTRACT FROM AUTHOR]

The James Webb Space Telescope (JWST) is frequently referred to as the follow-on mission to the Hubble Space Telescope (HST). The 'Webb' will be the biggest space telescope ever built and is expected to enable astounding new science. The observatory comprises a 6.5-m-diameter telescope with a segmented primary mirror and four high-performance optical science instruments. The JWST has mostly been optimized to work in the near- (0.6–5.0 μm) and mid-infrared (5.0–29 μm) wavelength regions. The project is a strong international partnership led by the National Aeronautics and Space Administration (NASA) with contributions from the European Space Agency (ESA) and the Canadian Space Agency (CSA). The observatory is currently scheduled for launch in early 2021 from Kourou, French Guyana, by an ESA-provided Ariane 5 rocket. This paper will focus on the European optical contribution to the mission, which mainly consists of two highly advanced optical science instruments: The multi-object near-infrared spectrograph (NIRSpec) and the mid-infrared instrument (MIRI). The opto-mechanical design considerations and the realization of both instruments will be described, and we will conclude with a short JWST project status report and future outlook. [ABSTRACT FROM AUTHOR]

The E3 ubiquitin ligase HMG-CoA reductase degradation protein 1 (Hrd1) is a key enzyme for ER-associated degradation of misfolded proteins. Its role in ischemic heart disease has not been fully elucidated. Here, we investigated its effect on oxidative status and cell survival in cardiac ischemia-reperfusion injury (MIRI). We found that virus-induced down-regulation of Hrd1 expression limited infarct size, decreased creatinine kinase (CK) and lactate dehydrogenase (LDH), and preserved cardiac function in mice subjected to left anterior descending coronary artery ligation and reperfusion. Silencing of the Hrd1 gene also prevented the ischemia/reperfusion (I/R)-induced (i) increase in dihydroethidium (DHE) intensity, mitochondrial production of reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO), (ii) decrease in total antioxidant capacity (T-AOC) and glutathione (GSH), (iii) disruption of mitochondrial membrane potential, and (iv) increase in the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) in ischemic heart tissue. In addition, down-regulation of Hrd1 expression prevented the abnormally increased caspase-3/caspase-9/Bax expression and decreased Bcl-2 expression in ischemic heart tissue of I/R mice. Further analysis showed that the I/R stimulus reduced peroxisome proliferation activated receptor α (PPARα) expression in ischemic heart tissue, which was partially prevented by down-regulation of Hrd1. Pharmacological inhibition of PPARα was able to abolish the preventive effect of down-regulation of Hrd1 on oxidative stress, endoplasmic reticulum stress, and cellular apoptosis in ischemic heart tissue. These data suggest that down-regulation of Hrd1 protects the heart from I/R-induced damage by suppressing oxidative stress and cellular apoptosis likely through PPARα. [ABSTRACT FROM AUTHOR]

The Shallow Radar (SHARAD) on the Mars Reconnaissance Orbiter (MRO), used to search for subsurface water ice, requires corrections to range delays and image distortions caused by radiowave propagation through the Martian ionosphere. These corrections yield a phase parameter that is linearly correlated with values of the total electron content (TEC), defined as the integral of the electron density profile Ne( h). This new database has been validated using previous observational patterns of TEC magnitudes and variability versus latitude, local time, and season. The SHARAD TEC data span the years 2007 to 2014, providing the first opportunity to study solar cycle effects upon daytime TEC magnitudes. A parameterization of TEC versus solar zenith angle and solar flux, within the context of photochemical equilibrium theory, provides a flexible TEC module for the Mars Initial Reference Ionosphere (MIRI) model. A high spatial resolution study of TEC variability in the southern hemisphere confirmed a previously tentative conclusion about daytime TEC morphology controlled by the local inclination angles of crustal magnetic fields. [ABSTRACT FROM AUTHOR]

This study presents the potential of harvesting wind energy in Sarawak, Malaysia based on the ground station and prediction models. A topographical feedforward neural network (T-FFNN) is proposed as an alternative to predict the wind speed in the areas where wind speed measurements are not done. The model has nine meteorological, geographical and topographical parameters as inputs while monthly winds speed as an output variable. The suitability of the model was assessed based on the mean absolute percentage error (MAPE). The most effective network design with lowest MAPE of 3.4% and correlation R between the predicted and the ground station wind speed of 0.91 was obtained. The study shows the characteristics of wind speed at 10–40 m heights. For the wind speed distribution, in addition to the widely applied Weibull and Rayleigh models, Gamma, Erlang and Lognormal are included. It was found that Gamma and Weibull outperform the others based on the three goodness-of-fit (GOF). An assessment of wind energy potential was performed using the measured and predicted wind speed data. The outcomes show that wind power density falls within class 1 ( P D ≤ 100 W/m 2 ). Final results from micro-sitting investigating the performance of annual energy output (AEO) in the examined area are presented. The results indicate that the AEO differs with altitudes. In all the examined areas, the AEO values varied from about 5800–13,622 kWh/year. These results show the possibility of using wind energy for small-scale purpose. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of nicorandil preconditi oning on mitochondiral DNA 4834 bp deletion of myochondial ischemia-reperfusion injury in rats. Methods: Weighing 200 g-300 g, aged between 7-9 weeks fifty healthy male Sprague-Dawley(SD) rats were random Ly allocated into 5 groups(n=10 each): group Sham, group MIRI,group IPC, group Nic and group Nic+5-HD. The animals were sacrificed and myochondial tissues were collected, mitochondiral DNA was isolation. The mitochondrial DNA4834 bp deletion mutation was detected by nested-PCR(nested polymers chain reaction) technique. Results: The frequence of the mitochondrial DNA 4834 bp deletion mutation of MIRI group, IPC group, Nic group and Nic+5-HD group were 100%, 20%, 30%, 89%.The mt DNA4834 bp mutation frequency of Nic group was significantly lower than MIRI group and Nic+5-HD group(P<0.05), there were no significant difference between Nic group and IPC group(P<0.05). Conclusion: Nicorandil precondition decrease the mt DNA4834 bp deletion mutation of rats. [ABSTRACT FROM AUTHOR]

This paper discusses the petroleum geology-related sites in and around Miri, in the state of Sarawak, Malaysia and their potentials as geotourism resources. Desk study was conducted by reviewing some literatures related to the topic and the study area. A field visit was conducted in May 2014 to observe the recent situation of all sites in details. There are some geological/natural and manmade features in and around the city which are closely related to petroleum geology. The Canada hill (anticline), a unique tectonic feature which emerged from the surrounding coastal plain, is a petroleum trap and used to be the location of many oil wells. On top of this hill is the location of the first oil well (called "the Grand Old Lady") and Miri Petroleum Museum. The deltaic sandstone outcrops of Miri Formation (such as the Airport Road outcrop and other outcrops around Miri) are very ideal outcrops of sandstone reservoirs. Oil seeps, mud volcanoes, and oil sands are some evidences of petroleum occurrences in and around the city. Niah Caves can be seen as an analogue of carbonate reservoirs. All these sites and features can attract people to visit the city, not only geologists and geology students who want to study the petroleum geology of Miri area, but also the common people who are interested in such a field. [ABSTRACT FROM AUTHOR]