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Aim: To investigate the association of DNA methylation, genetic polymorphisms and mRNA level of aminolevulinate synthase 1 (ALAS1) with antituberculosis drug-induced liver injury (AT-DILI) risk.Methods: Based on a 1:1 matched case-control study with 182 cases and 182 controls, one CpG island and three single nucleotide polymorphisms (SNPs) were detected. ALAS1 mRNA level was detected in 34 samples.Results: Patients with methylation status were at high risk of AT-DILI (odds ratio: 1.567, 95% CI: 1.015-2.421, p = 0.043) and SNP rs352169 was associated with AT-DILI risk (GA vs. GG, odds ratio: 1.770, 95% CI: 1.101-2.847, p = 0.019). ALAS1 mRNA level in the cases was significantly lower than that in the controls (0.75 ± 0.34 vs. 1.00 ± 0.42, p = 0.021).Conclusion: The methylation status and SNP rs352169 of ALAS1 were associated with AT-DILI risk.

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Background: Congenital sideroblastic anemia (CSA) constitutes a group of inherited erythropoietic disorders. Some affect mainly or exclusively erythroid cells; other syndromic forms occur within multisystem disorders with extensive nonhematopoietic manifestations. In this study, we have performed clinical and molecular investigations on a 10-year-old boy suspected of having CSA. Methods: Routine blood examination, peripheral blood and bone marrow smears, and serum iron tests were performed. Gene mutation analysis was conducted using whole-exome sequencing (WES) and the results were confirmed using Sanger sequencing. Furthermore, the functional impact of the identified variant was assessed/predicted with bioinformatics methods. Results: The patient presented with severe microcytic anemia (hemoglobin, 50 g/L), iron overload and ring sideroblasts in the bone marrow. Moreover, WES revealed the presence of a hemizygous missense variant in ALAS2 (c.1102C > T), changing an encoded arginine to tryptophan (p. Arg368Trp). This variant was verified via Sanger sequencing, and neither of the parents carried this variant, which was suspected to be a de novo variant. Using in silico analysis with four different software programs, the variant was predicted to be harmful. PyMol and LigPlot software showed that the p. Arg368Trp variant may result in changes in hydrogen bonds. The patient was treated with vitamin B6 combined with deferasirox. After 6 months, the hemoglobin increased to 99 g/L and the serum ferritin decreased significantly. Conclusion: We report a novel pathogenic variant in the ALAS2 gene (c.1102C > T:p. Arg368Trp), which caused CSA in a 10-year-old boy. Mutational analysis is important in patients with CSA when family history data are unavailable. Anemia due to the ALAS2 Arg368Trp variant responds to pyridoxine supplements.

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A rapid, sensitive and specific test for blood is reported based on a novel application of recombinase polymerase amplification integrated with CRISPR-Cas and lateral flow assay (LFA). The blood specific marker ALAS2 was used as the target to record the presence of blood. The assay used either RNA extracted from a body fluid as a template, or omitting this extraction step and using a direct approach where the questioned body fluid was added directly to the assay. The assay only detected blood (all peripheral blood and some menstrual blood samples) and no other body fluid (semen, saliva, or vaginal fluid). The limit of detection varied from an initial template of 0.195 ng extracted RNA (27 dilution) or 0.0218 µL (26 dilution) liquid peripheral blood. The assay gave the expected result when peripheral blood was mixed with saliva: ratios of peripheral blood/saliva at 19:1, 3:1, 1:1, 1:3 and 1:19 all gave a positive result using extracted RNA. By contrast, only three ratios of peripheral blood and saliva gave a positive result for blood (19:1, 3:1 and 1:1) when adding these two body fluids directly. When peripheral blood was mixed with semen there was a strong inhibition of the assay and ALAS2 could only be detected at ratio of 19:1 using RNA. Using reconstituted peripheral bloodstains gave comparable results to liquid peripheral blood. This is the first application of RT-RPA integrated CRISPR and combined with a LFA assay to detect body fluid-specific RNA. The proposed method opens up the potential to perform this method remote from laboratories such as at crime scenes.

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Sideroblastic anaemias are a diverse group of congenital and acquired bone marrow failure disorders marked by the presence of ring sideroblasts, ineffective erythropoiesis, and systemic iron overload. Congenital Sideroblastic anaemia (CSA) is mainly caused by gene mutations associated with heme synthesis, iron-sulfur [Fe-S] cluster, and mitochondrial protein synthesis pathways. The most prevalent form of CSA is caused by mutations in the erythroid-specific -amino levulinate synthase (ALAS2) gene, which encodes the first enzyme in the heme synthesis pathway in red blood cells. The second most prevalent form of CSA is caused by a mutation in the Solute carrier family 25 member 38 (SLC25A38) gene, which codes for an erythroid-specific protein of the inner mitochondrial membrane. Additionally, 15-20 genes are altogether associated with CSA. In this study, we aim to identify the CSA patients, understand their genetics and establish genotype-phenotype correlation. We have identified fifteen cases of CSA using our targeted NGS (t-NGS) panel. The major clinical findings in our cohort were microcytic anaemia, ring sideroblasts, and dyserythropoiesis in the bone marrow. Currently, two patients are responsive to pyridoxine, while the rest are on blood transfusion support. We have identified ten variants in three different genes of CSA (ALAS2, SLC25A38 & HSPA9). Five patients harbour four hemizygous variants- p.Ala282Ser, p.Arg170Cys, p.Arg204Gln and exon 2 duplication in the ALAS2 gene. In seven patients, we have identified three homozygous mutations - p.Pro190Arg, p.Arg187Gln and p.Arg134Cys in the SLC25A38 gene. These mutations have been predominantly identified in the European population. Three patients revealed three heterozygous variants p. Thr463Ile, D326Tyr, and Arg284Trp in the HSPA9 gene. PyMoL was used to evaluate the functional effects of these variations and understand their effect on the structure of the protein. We believe that by combining a bone marrow examination with genetic sequencing, CSA patients can acquire a definitive diagnosis.

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LONP1 is the principal AAA+ unfoldase and bulk protease in the mitochondrial matrix, so its deletion causes embryonic lethality. The AAA+ unfoldase CLPX and the peptidase CLPP also act in the matrix, especially during stress periods, but their substrates are poorly defined. Mammalian CLPP deletion triggers infertility, deafness, growth retardation, and cGAS-STING-activated cytosolic innate immunity. CLPX mutations impair heme biosynthesis and heavy metal homeostasis. CLPP and CLPX are conserved from bacteria to humans, despite their secondary role in proteolysis. Based on recent proteomic-metabolomic evidence from knockout mice and patient cells, we propose that CLPP acts on phase-separated ribonucleoprotein granules and CLPX on multi-enzyme condensates as first-aid systems near the inner mitochondrial membrane. Trimming within assemblies, CLPP rescues stalled processes in mitoribosomes, mitochondrial RNA granules and nucleoids, and the D-foci-mediated degradation of toxic double-stranded mtRNA/mtDNA. Unfolding multi-enzyme condensates, CLPX maximizes PLP-dependent delta-transamination and rescues malformed nascent peptides. Overall, their actions occur in granules with multivalent or hydrophobic interactions, separated from the aqueous phase. Thus, the role of CLPXP in the matrix is compartment-selective, as other mitochondrial peptidases: MPPs at precursor import pores, m-AAA and i-AAA at either IMM face, PARL within the IMM, and OMA1/HTRA2 in the intermembrane space.

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Background: Aortic aneurysm, characterized by abnormal dilation of the aorta, poses significant health risks. This study aims to investigate the interaction between 5-aminolevulinate synthase 2 (ALAS2) and GATA-binding protein 1 (GATA1) in ferroptosis and oxidative stress responses in aortic aneurysm. Methods: A weighted gene co-expression network analysis (WGCNA) was performed on the differentially expressed genes (DEGs) within the GSE9106 dataset to identify the key module. Subsequently, protein-protein interaction (PPI) network analysis was performed on the key module. Mouse aortic vascular smooth muscle cells (MOVAS) were treated with hydrogen peroxide (H2O2) to induce oxidative stress, and ferroptosis inducers and inhibitors were added to evaluate their effects on iron content and oxidative stress markers. Through a series of in vitro cellular experiments, we assessed cell viability, expression levels of GATA1 and iron mutation-associated proteins, as well as cellular phenotypes such as inflammatory responses and apoptosis rates. Results: Three candidate genes (ALAS2, GYPA, and GYPB) were upregulated in the thoracic aortic aneurysm (TAA) samples of the GSE9106 dataset. The H2O2 treatment increased the MOVAS cells' iron content and oxidative stress, upregulated ALAS2 protein levels, and decreased the ferroptosis-related protein levels. ALAS2 overexpression reversed H2O2-induced apoptosis and increased the inflammatory cytokine levels. Additionally, the knockdown of GATA1 partially reversed the protective mechanism of overexpressed ALAS2 on H2O2-induced ferroptosis. Conclusions: ALAS2 overexpression reduced H2O2-induced oxidative damage and iron-induced apoptosis in MOVAS cells, and GATA1 knockdown partially reversed this protective effect. These findings suggested that the ALAS2 and GATA1 regulatory pathways may be potential therapeutic targets in aortic aneurysms.

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This study developed an advanced 850 nm centered distributed Bragg reflector (DBR) (broadband DBR) composed of nanomaterial-based multiple structures to improve the optical efficiency of an 850 nm near-infrared light-emitting diode (NIR-LED). A combined 850 nm centered broadband DBR was fabricated by growing an 800 nm centered ten-pair DBR on a 900 nm centered ten-pair DBR (denoted as a combined DBR). The combined DBR exhibited a slightly wider peak band than conventional DBRs. Furthermore, the peak band width of the combined DBR significantly increased upon using a reflective AlAs buffer layer that reduced the overlapped reflection. The output power (20.5 mW) of NIR-LED chips using the combined DBR with an AlAs buffer layer exceeded that of a conventional 850 nm centered DBR (14.5 mW) by more than 40%. Results indicated that combining the optical conditions of wavelengths and the AlAs buffer layer effectively strengthened the broadband effect of the DBR and increased the optical efficiency of the 850 nm NIR-LED.

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Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthetic pathway, FLVCR1a influences TCA cycle cataplerosis, thus impacting TCA flux and interconnected metabolic pathways. This study reveals an unexplored link between FLVCR1a, heme synthesis, and cholesterol production in endothelial cells. Using cellular models with manipulated FLVCR1a expression and inducible endothelial-specific Flvcr1a-null mice, we demonstrate that FLVCR1a-mediated control of heme synthesis regulates citrate availability for cholesterol synthesis, thereby influencing cellular cholesterol levels. Moreover, alterations in FLVCR1a expression affect membrane cholesterol content and fluidity, supporting a role for FLVCR1a in the intricate regulation of processes crucial for vascular development and endothelial function. Our results underscore FLVCR1a as a positive regulator of heme synthesis, emphasizing its integration with metabolic pathways involved in cellular energy metabolism. Furthermore, this study suggests that the dysregulation of heme metabolism may have implications for modulating lipid metabolism. We discuss these findings in the context of FLVCR1a's potential heme-independent function as a choline importer, introducing additional complexity to the interplay between heme and lipid metabolism.

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The definition of cell metabolic profile is essential to ensure skeletal muscle fiber heterogeneity and to achieve a proper equilibrium between the self-renewal and commitment of satellite stem cells. Heme sustains several biological functions, including processes profoundly implicated with cell metabolism. The skeletal muscle is a significant heme-producing body compartment, but the consequences of impaired heme homeostasis on this tissue have been poorly investigated. Here, we generate a skeletal-muscle-specific feline leukemia virus subgroup C receptor 1a (FLVCR1a) knockout mouse model and show that, by sustaining heme synthesis, FLVCR1a contributes to determine the energy phenotype in skeletal muscle cells and to modulate satellite cell differentiation and muscle regeneration.

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Even though Pacific - Indian Ocean exchange [Indonesian Throughflow (ITF)] has been measured for the last three decades, the measurements of microplastic in the region is very limited. This study was the initial investigation of the vertical distribution of microplastic in the deep-sea areas across the ITF Pathway. Niskin water samples were utilized to obtain the samples from a water column in a range of 5 to 2450 m. A total of 924 microplastic particles with an average abundance of 1.062 ± 0.646. n/L were found in the water column. Our findings indicate that water temperature and water density are the most significant factors correlated to the microplastic concentration. This study will be the first report discussing the distribution of microplastics in the deep-sea water column that could be highly significant in determining the fate and transport of microplastic within Indonesian waters that exits into the Indian Ocean.

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Photodynamic therapy (PDT) is nowadays widely employed in cancer treatment. We sought to assess the efficacy of combining PDT with anti-programmed cell death protein 1 (PD1) and to investigate the associated mechanisms in nonsmall cell lung cancer (NSCLC). We established a xenograft tumor model in C57BL/6J mice using Lewis lung carcinoma (LLC) cells, recorded tumor growth, and quantified reactive oxygen species (ROS) levels using a ROS detection kit. Pathological changes were assessed through H&E staining, while immunofluorescence (IF) was used to determine the expression of CD8 and Foxp3. Transcriptomic analysis was conducted, analyzing differential expressed genes (DEGs) among control, PDT, and PDT combined with anti-PD1 (PDT+anti-PD1) groups. Functional enrichment analysis via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed. The Cancer Genome Atlas (TCGA) database was utilized to analyze the expression of aminolevulinate synthase gene (ALAS2), integrin alpha10 (ITGA10), ATP1A2, a disintegrin and metalloprotease 12 (ADAM12), and Lox1 in lung adenocarcinoma and adjacent tissues, with concurrent immune infiltration analysis. Quantitative real-time polymerase chain reaction and western blot were employed to measure mRNA and protein expression levels. Treatment with PDT combined with anti-PD1 significantly inhibited tumor growth and increased the number of CD8+ cells while decreasing Foxp3+ cells. Immune infiltration results presented ALAS2, ADAM12, and ITGA10 were associated with various types of T cells or macrophages. Additionally, the expression levels of EGFR, ERK, and PI3K/Akt were suppressed after PDT with anti-PD1 treatment. Our findings collectively suggest that PDT combined with anti-PD1 treatment could enhance the infiltration of CD8+ T cells, suppressing tumor growth, and this effect was associated with ALAS2, ITGA10, and ADAM12. The underlying mechanism might be linked to EGFR, ERK, and PI3K/Akt signaling. Overall, this study provides valuable insights into the application of PDT combined with anti-PD1 treatment in NSCLC.

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Heme is an iron-containing molecule essential for virtually all living organisms. However, excessive heme is cytotoxic, necessitating tight regulation of intracellular heme concentration. The acute hepatic porphyrias (AHPs) are a group of rare inborn errors of heme biosynthesis that are characterized by episodic acute neurovisceral attacks that are precipitated by various factors. The AHPs are often misdiagnosed, as the acute attack symptom are non-specific and can be attributed to other more common causes. Understanding how heme biosynthesis is dysregulated in AHP patients and the mechanism by which acute attacks are precipitated will aid in accurate and rapid diagnoses, and subsequently, appropriate treatment of these disorders. Therefore, this review article will focus on the biochemical and molecular changes that occur during an acute attack and present what is currently known regarding the underlying pathogenesis of acute attacks.

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5-Aminolevulinic acid (ALA) is a precursor of heme and a natural amino acid synthesized in the cells of most living organisms. Currently, ALA is used as an ingredient in pharmaceuticals, supplements, cosmetics, feed, fertilizers, and other products. ALA is mainly produced by industrial fermentation by the photosynthetic bacterium Rhodobacter sphaeroides. In this study, we tried to improve the ALA productivity by R. sphaeroides using a genetic strategy to highly express ALA synthase (ALAS) genes. We inserted a constitutive promoter (PrrnB or Prsp_7571) upstream of genes encoding ALAS (hemA and/or hemT) to construct strains that constitutively express ALAS. The highest transcript levels of hemA were observed in the strain where PrrnB was inserted into the hemA promoter region and were 3.5-fold higher than those in the wild-type. The highest transcript levels of hemT were observed in the strain where PrrnB was inserted into the hemT promoter region and were 46-fold higher than those in the wild-type. The maximum ALAS activity was observed in crude cell extracts of the strain where PrrnB was inserted into the hemT promoter region under optimized growth conditions that was 2.7-fold higher than that in the wild type. This strain showed 12-fold accumulation of ALA compared to the wild-type. Thus, we improved ALA productivity without using exogenous DNA sequences. In the future, further improvement in ALA productivity may be expected by applying this approach to current industrial ALA-producing bacteria.

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Understanding and control of thermal transport in solids at the nanoscale are crucial in engineering and enhance the properties of a new generation of optoelectronic, thermoelectric and photonic devices. In this regard, semiconductor superlattice structures provide a unique platform to study phenomena associated with phonon propagations in solids such as heat conduction. Transient X-ray diffraction can directly probe atomic motions and therefore is among the rare techniques sensitive to phonon dynamics in condensed matter. Here, optically induced transient heat conduction in GaAs/AlAs superlattice structures is studied using the EIGER2 detector. Benchmark experiments have been performed at the Austrian SAXS beamline at Elettra-Sincrotrone Trieste operated in the hybrid filling mode. This work demonstrates that drifts of experimental conditions, such as synchrotron beam fluctuations, become less essential when utilizing the EIGER2 double-gating mode which results in a faster acquisition of high-quality data and facilitates data analysis and data interpretation.

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Pollution of the Arctic Ocean by potentially toxic elements (PTEs) is a current environmental problem. Humic acids (HAs) play an important role in the regulation of PTE mobility in soil and water. The permafrost thaw releases ancient organic matter (OM) with a specific molecular composition into the Arctic watersheds. This could affect the mobility of PTEs in the region. In our study, we isolated HAs from two types of permafrost deposits: the Yedoma ice complex, which contains pristine buried OM, and the alas formed in the course of multiple thaw-refreezing cycles with the most altered OM. We also used peat from the non-permafrost region as the recent environmental endmember for the evolution of Arctic OM. The HAs were characterized using 13C NMR and elemental analysis. Adsorption experiments were conducted to assess the affinity of HAs for binding Cu2+ and Ni2+. It was found that Yedoma HAs were enriched with aliphatic and N-containing structures as compared to the much more aromatic and oxidized alas and peat HAs. The adsorption experiments have revealed that the peat and alas HAs have a higher affinity for binding both ions as compared to the Yedoma HAs. The obtained data suggest that a substantial release of the OM from the Yedoma deposits due to a rapid thaw of the permafrost might increase the mobility of PTEs and their toxicity in the Arctic Ocean because of much lesser "neutralization potential".

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Food availability is an important factor affecting the feeding strategies of animals. Primate species living in habitats with high human activity have the potential to employ unique strategies to utilize human food resources. This study describes the feeding ecology of provisioned free-ranging long-tailed macaques (Macaca fascicularis) inhabiting Alas Purwo National Park, East Java, Indonesia. The activity budgets, dietary compositions, vertical usage, and ranging patterns of macaques were recorded between October 2021 and March 2022, and their relationships with the number of visitors (a proxy of human food availability) were examined. The macaques consumed more human food (mean ± SD: 53.9 ± 25.6%) than natural food (43.8 ± 25.5%), followed by unidentified food (2.3 ± 6.3%). Human food has several effects on the behavioral ecology of macaques, including reduced movement and increased social activity in response to the number of visitors, decreased consumption of natural food, frequent use of the ground and subcanopy strata, and decreased home range when the number of visitors increases. Thus, the relative importance of human food has substantially changed the essential behavioral ecology of provisioned macaque troops. Understanding the behavioral plasticity of macaques, particularly their responses to anthropogenic effects, could guide and contribute to the formulation of conservation policies and management plans.

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Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder affecting women at reproductive age. The therapeutic effect of electroacupuncture (EA) on PCOS has been revealed, while the anti-PCOS mechanisms of EA have not been fully explored. In this study, PCOS were induced in rats by daily injection with dehydroepiandrosterone (DHEA) for 20 days and EA treatment was performed for 5 weeks. The mRNA expression profiles in ovarian tissues from control, PCOS, and EA-treated rats were examined by high-throughput mRNA sequencing. 5'-aminolevulinate synthase 2 (Alas2), a vital rate-limiting enzyme of the heme synthesis pathway, was selected to be further studied. PCOS led to the upregulation of Alas2 mRNA, whereas EA treatment restored this change. In vitro, primary ovarian granulosa cells (GCs) were challenged with H2O2 to mimic the oxidative stress (OS) state in PCOS. H2O2 induced apoptosis, OS, mitochondrial dysfunction, as well as Alas2 overexpression in GCs, while lentivirus-mediated Alas2 knockdown evidently restrained the above impairments. In summary, this study highlights the crucial role of Alas2 in cell apoptosis, OS, and mitochondrial dysfunction of PCOS GCs and provides potential therapeutic candidates for further investigation on PCOS treatment.

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ALAS1 is a member of the α-oxoamine synthase family, which is the first rate-limiting enzyme for heme synthesis and is important for maintaining intracellular heme levels. In the ovary, ALAS1 is associated with the regulation of ovulation-related mitochondrial P450 cytochromes, steroid metabolism, and steroid hormone production. However, there are few studies on the relationship between ALAS1 and reproductive traits in goats. In this study, a mutation located in the promoter region of ALAS1 (g.48791372C>A) was found to be significantly (p < 0.05) associated with the kidding number of Yunshang black goats. Specifically, the mean kidding number in the first three litters and the kidding numbers of all three litters were significantly (p < 0.05) higher in individuals with the CA genotype or AA genotype than in those with the CC genotype. To further investigate the regulatory mechanism of ALAS1, the expression of ALAS1 in goat ovarian tissues with different genotypes was verified by real-time quantitative PCR. The results showed that the expression of ALAS1 was significantly higher in the ovaries of individuals with AA genotype than those with AC and CC genotypes (p < 0.01), and the expression trend of transcription factor ASCL2 was consistent with ALAS1. Additionally, the ALAS1 g.48791372C>A mutation created a new binding site for the transcription factor ASCL2. The luciferase activity assay indicated that the mutation increased the promoter activity of ALAS1. Overexpression of the transcription factor ASCL2 induced increased expression of ALAS1 in goat granulosa cells (p < 0.05). The opposite trend was shown for the inhibition of ASCL2 expression. The results of real-time quantitative PCR, EdU and Cell Counting Kit-8 assays indicated that the transcription factor ASCL2 increased the proliferation of goat granulosa cells by mediating the expression of ALAS1. In conclusion, the transcription factor ASCL2 positively regulated the transcriptional activity and expression levels of ALAS1, altering granulosa cell proliferation and the kidding number in goats.

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Myocardial infarction (MI) is one of the important factors leading to death in today's society. Therefore, to study the related mechanism of MI and reduce myocardial ischemia-reperfusion injury is an important link to reduce MI injury. MI mice in vivo and cell model in vitro were constructed. The cardiac function and MI area of mice were detected, and myocardial tissue injury was detected by HE staining. ALAS2 expression in mice myocardial tissue was detected by IHC. The expressions of lncRNA-SNHG8, METTL3, PTBP1 and ALAS2 in myocardial tissue or cardiomyocytes were detected by qRT-PCR assay. MTT assay was used to measured viability of cardiomyocytes. The oxidative stress level in myocardial tissue or cardiomyocytes was detected by ELISA assay and ROS assay. RIP-qPCR and RNA pulldown assays determined the interaction between METTL3 and lncRNA-SNHG8, as well as PTBP1 and ALAS2. lncRNA-SNHG8 knockdown in MI mice was reduced myocardial infarction size, alleviated myocardial tissue injury and oxidative stress, and inhibited ALAS2 expression in myocardial tissue. RNA pulldown and RIP assays showed that lncRNA-SNHG8 binged with PTBP1 and PTBP1 interacted with ALAS2 mRNA. Knockdown of lncRNA-SNHG8, METTL3 or PTBP1 in MI cells enhanced viability of myocardial cells, attenuated ROS release and MDA level, increased SOD level, alleviated oxidative stress. ALAS overexpression attenuated the corresponding effect of knockdown of lncRNA-SNHG8 and/or PTBP1 on MI cells. In sum, our paper is demonstrated for the first time that METTL3 can promote lncRNA-SNHG8 through m6A modification, thereby regulating ALAS2 to induce oxidative stress and aggravate myocardial injury.

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