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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.

Background Congenital sideroblastic anemia (CSA) and thalassemia are both hereditary disorders of erythropoiesis, primarily affecting erythroid cells. Their typical manifestations include anemia and iron overload. In this study, we conducted clinical and molecular analyses on a male patient who was concurrently diagnosed with thalassemia and CSA. Methods The patient underwent a series of tests including complete blood count, bone marrow smear, and serum ferritin levels. Whole exome sequencing technology was employed for genetic mutation analysis, and bioinformatics methods were utilized to assess the functional impact of the predicted variants. Results The patient was previously diagnosed with alpha thalassemia (with genotype of -- SEA /-α 4.2 ), and has been receiving frequent blood transfusions over the past two years, presenting with severe anemia (Hb level of 44 g/L), iron overload, and 52% ring sideroblasts in the bone marrow. Whole exome sequencing revealed a hemizygous nonsense mutation (c.224 C > A) in the 5-aminolevulinate synthase (ALAS2) gene, which introduces a premature stop codon at the 75th amino acid position in the N-terminal region (P.S75X). Family analysis showed that the patient, her mother, and her sister all carry this variant, suggesting it is a de novo mutation. Computational analysis using various online software tools predicted the variant to be deleterious. The patient was treated with a combination of vitamin B₆, folic acid, and deferasirox. After six months, the Hb level increased to 104 g/L, while the serum ferritin level initially rose and subsequently decreased. Conclusion This study identified and reported a novel variant, ALAS2 c.224 C > A (P.S75X), which led to the co-occurrence of sideroblastic anemia in a male patient with thalassemia. The anemia symptoms induced by this variant were responsive to pyridoxine (vitamin B₆) supplementation therapy.

X-linked sideroblastic anemia (XLSA) is a hereditary disorder affecting heme biosynthesis, caused by mutations in the ALAS2 gene, which encodes the erythroid-specific enzyme 5-aminolevulinate synthase. This enzyme, which requires pyridoxal 5’-phosphate (PLP) as a cofactor, catalyzes the first and rate-limiting step of heme synthesis in erythroid cells. XLSA is characterized by hypochromic microcytic anemia and ring sideroblasts in bone marrow, with most patients showing variable degrees of response to pyridoxine supplementation; however, female carriers of ALAS2 mutations often present a distinct clinical phenotype. A comprehensive review of the literature reveals over 100 distinct ALAS2 mutations linked to XLSA in more than 240 families. Here, we report seven new patients (four female cases) initially diagnosed with various conditions, later confirmed to have X-linked Sideroblastic Anemia due to ALAS2 mutations through genetic analysis. Among these, five represent novel ALAS2 mutations, including the first ever reported stop-loss mutation in ALAS2 associated with XLSA rather than X-linked dominant protoporphyria (XLDPP). Computational modelling of six reported cases revealed that four mutations significantly impact protein structure, conformation and cofactor interaction, consistent with our enzymatic assays demonstrating reduced ALAS2 activity. Furthermore, X-chromosome studies in female probands revealed a pronounced skewing of X-chromosome, which may provide an explanation for their distinct clinical manifestations in females.

SARS-CoV-2 variants of concern (VOC) have been associated with increased viral transmission and disease severity. We investigated the mechanisms of pathogenesis caused by variants using a host blood transcriptome profiling approach. We analysed transcriptional signatures of COVID-19 patients comparing those infected with wildtype (wt), alpha, delta or omicron strains seeking insights into infection in Asymptomatic cases. Comparison of transcriptional profiles of Symptomatic and Asymptomatic COVID-19 cases showed increased differentially regulated gene (DEGs) of inflammatory, apoptosis and blood coagulation pathways, with decreased T cell and Interferon stimulated genes (ISG) activation. Between SARS-CoV-2 strains, an increasing number of DEGs occurred in comparisons between wt and alpha (196), delta (1425) or, omicron (2313) infections. COVID-19 cases with alpha or, delta variants demonstrated suppression transcripts of innate immune pathways. EGR1 and CXCL8 were highly upregulated in those infected with VOC; heme biosynthetic pathway genes (ALAS2, HBB, HBG1, HBD9) and ISGs were downregulated. Delta and omicron infections upregulated ribosomal pathways, reflecting increased viral RNA translation. Asymptomatic COVID-19 cases infected with delta infections showed increased cytokines and ISGs expression. Overall, increased inflammation, with reduced host heme synthesis was associated with infections caused by VOC infections, with raised type I interferon in cases with less severe disease.

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.

Neonatal necrotizing enterocolitis (NEC) is an intestinal disease that occurs in the neonatal period. The purpose of this study was to investigate the role of 5′‐aminolevulinate synthase 2 (ALAS2) in NEC‐induced intestinal injury. In a neonatal mouse, NEC model was induced by high‐osmolarity formula and hypoxia‐cold stress, and ALAS2 expression was significantly downregulated in ileal tissues ( p < 0.01), coinciding with elevated oxidative stress (increased Fe 2+ /malondialdehyde [MDA] and decreased superoxide dismutase [SOD]), inflammation (increased TNF‐α/interferon‐gamma [IFN‐γ]), and ferroptosis activation (increased acyl‐CoA synthetase long‐chain family member 4 [ACSL4] and decreased ferritin heavy chain 1 [FTH1] with mitochondrial shrinkage). In vitro, tumor necrosis factor‐alpha (TNF‐α)/IFN‐γ‐treated intestinal epithelial cell (IEC) exhibited progressive ALAS2 suppression and increased necrosis. Crucially, lentivirus‐mediated ALAS2 overexpression reversed these effects, reducing cell necrosis by 22% while suppressing ferroptosis markers (Fe 2+ accumulation, lipid reactive oxygen species [ROS], and mitochondrial depolarization) and oxidative damage (decreased MDA and restored glutathione [GSH]/catalase [CAT]/SOD). Untargeted metabolomics further revealed ALAS2‐mediated modulation of nutrient metabolism and redox pathways. Collectively, ALAS2 ameliorates NEC by blocking oxidative stress‐driven ferroptosis in IECs, proposing a novel therapeutic target.

Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of ALAS2 mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria.

X‐linked sideroblastic anaemia (XLSA) is a rare hereditary disorder caused by mutations in the ALAS2 gene, essential for haem biosynthesis. We report two male siblings, the first of whom developed severe microcytic hypochromic anaemia requiring regular transfusions, iron chelation and an allogeneic bone marrow transplant, while his brother displayed only mild microcytic hypochromic indices without anaemia. Initial genetic screening did not identify a pathogenic variant. However, duo exome sequencing later revealed an intronic ALAS2 mutation, initially categorised as of uncertain significance and subsequently reclassified as pathogenic. This case underscores the diagnostic challenges posed by intronic mutations and the highly variable expressivity of XLSA, even among siblings. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

X-linked sideroblastic anemia (XLSA) (MIM 300752) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. It is due to mutations of the erythroid-specific enzyme ALAS2 , the first enzyme of the heme biosynthetic pathway. Herein, we report a novel 11-bp deletion in exon 11 leading to a frameshift in the C-terminal region of the ALAS2 gene with a non-functional longer polypeptide of 614 amino acids leading to a loss-of-function mutation manifested as an X-linked sideroblastic anemia phenotype. The proband was a 29-year-old man with moderately severe microcytic hypochromic anemia with splenomegaly and increased ring sideroblasts in the bone marrow with considerable iron overload. Sanger sequencing documented a missense mutation leading to a frameshift with an elongated polypeptide of 614 AA instead of the normal 587 AA protein c.1743_1753 del (p.Gln581Hisfs*35). This mutation affected the interaction with cofactor pyridoxal 5′-phosphate since the patient’s hemoglobin improved with oral administration of pyridoxine tablets. His iron overload also responded to sustained oral iron chelation therapy with deferasirox. The screening of the entire family’s kindred revealed that two other male siblings were also hemizygous for the same mutation with hypochromic microcytic anemia and tissue iron overload, whereas, three female siblings and their mother were heterozygous for the mutant allele. They did not have anemia or iron overload.

Background X-linked sideroblastic anaemia (XLSA) is commonly due to mutations in the ALAS2 gene and predominantly affects hemizygous males. Heterozygous female carriers of the ALAS2 gene mutation are often asymptomatic or only mildly anaemic. XLSA is usually characterized by microcytic erythrocytes (reduced mean corpuscular volume (MCV)) and hypochromia, along with increased red cell distribution width. However, in females with XLSA the characteristic laboratory findings can be dimorphic and present with macrocytic (elevated MCV) in addition to microcytic red cells. Case presentation We report a case of fetal anaemia, presenting in the early third trimester of pregnancy, in a female fetus. Ultrasound findings at 29 weeks were of cardiomegaly, prominent umbilical veins, a small rim of ascites, and mean cerebral artery peak systolic velocity (PSV) value above 1.5 Multiples of the Median (MoM). She underwent non-invasive prenatal testing that determined the rhesus genotype of the fetus to be rhesus B negative. No red blood cell antibodies were reported. Other investigations to determine the underlying cause of fetal anaemia included microarray comparative genomic hybridization, serology to exclude congenital infection and a peripheral blood film and fetal bilirubin to detect haemolysis. The maternal grandmother had a history of sideroblastic anaemia diagnosed at the age of 17 years. The mother had mild macrocytic anaemia with haemoglobin of 10.4 g/dl and MCV of 104 fl. The fetal anaemia was successfully treated with two in utero transfusions (IUTs), and delivery occurred via caesarean section at 37 weeks of gestation. The red cell gene sequencing in both the mother and fetus were heterozygous for an  ALAS2  mutation causing in utero manifestations of XLSA. The haemoglobin on discharge to the local hospital at five days of age was 19.1 g/dl. Subsequently, the infant became anaemic, requiring regular 3–4 monthly blood transfusions and demonstrating overall normal development. Her anaemia was unresponsive to pyridoxine. Conclusions This is one of four cases reporting multiple female members presenting with discordant clinical features of XLSA from being entirely asymptomatic to hydropic in utero. Our report is novel in that there are no previous cases in the literature of anaemia in a female fetus heterozygous for  ALAS2  mutation.