Cystathionine beta-Synthase in hypoxia and ischemia/reperfusion: A current overview.

Besides its presence in the liver, brain, pancreas, and kidney, Cystathionine beta-Synthase (CBS) is also found in many other tissues, where it acts through regulation of hydrogen sulfide (H2S) generation and homocysteine (Hcy) metabolism, to interact with other molecules during hypoxia and ischemia/reperfusion (I/R). Despite all the advances accumulated in decades of research on CBS, there are still controversies, and the role of CBS in many tissues during hypoxia and I/R is still unclear. Herein, we overviewed the expression level, the role, and the mechanism through which CBS interacts with other molecules during hypoxia and I/R processes in tissues of humans and other organisms. CBS appeared to be deregulated under hypoxia and I/R, after which it mostly conduces the reparation in the concerned tissue after damage; however, it has been described that CBS could also play pathological effects (exacerbating the damage). From all findings, it emerges that variations in CBS expression in these conditions depend on the organism, tissue, or subcellular localization, CBS could play both protective and pathological effects; and artificially controlling CBS expression may help to provide novel strategies for treatment or prevention of hypoxia and I/R -related injury.

Voltage-Gated Sodium Channel ß1 Gene: An Overview.

BACKGROUND: Voltage-gated sodium channels are protein complexes composed of 2 subunits, namely, pore-forming α- and regulatory ß-subunits. A ß-subunit consists of 5 proteins encoded by 4 genes (i.e., SCN1B-SCN4B). SUMMARY: ß1-Subunits regulate sodium ion channel functions, including gating properties, subcellular localization, and kinetics. Key Message: Sodium channel ß1- and its variant ß1B-subunits are encoded by SCN1B. These variants are associated with many human diseases, such as epilepsy, Brugada syndrome, Dravet syndrome, and cancers. On the basis of previous research, we aimed to provide an overview of the structure, expression, and involvement of SCN1B in physiological processes and focused on its role in diseases.

The Role of miR-210 in the Biological System: A Current Overview.

BACKGROUND: MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19-23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms. SUMMARY: miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. Key Message: miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.

Can miRNAs in MSCs-EVs Offer a Potential Treatment for Hypoxic-ischemic Encephalopathy?

Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition resulting from impaired oxygen and blood flow to the brain during birth, leading to neuroinflammation, neuronal apoptosis, and long-term neurological deficits. Despite the use of therapeutic hypothermia, current treatments remain inadequate in fully preventing brain damage. Recent advances in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) offer a novel, cell-free therapeutic approach, as these EVs can cross the blood-brain barrier (BBB) and deliver functional microRNAs (miRNAs) to modulate key pathways involved in inflammation and neuroprotection. This review examines how specific miRNAs encapsulated in MSC-EVs-including miR-21, miR-124, miR-146, and the miR-17-92 cluster-target the complex inflammatory responses that drive HIE pathology. By modulating pathways such as NF-κB, STAT3, and PI3K/Akt, these miRNAs influence neuroinflammatory processes, reduce neuronal apoptosis, and promote tissue repair. The aim is to assess the therapeutic potential of miRNA-loaded MSC-EVs in mitigating inflammation and neuronal damage, thus addressing the limitations of current therapies like therapeutic hypothermia.

Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren's syndrome based on integrated bioinformatics and single-cell RNA-seq analysis.

Background: Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) are common systemic autoimmune diseases that share a wide range of clinical manifestations and serological features. This study investigates genes, signaling pathways, and transcription factors (TFs) shared between SLE and pSS. Methods: Gene expression profiles of SLE and pSS were obtained from the Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were conducted to identify shared genes related to SLE and pSS. Overlapping genes were then subject to Gene Ontology (GO) and protein-protein interaction (PPI) network analyses. Cytoscape plugins cytoHubba and iRegulon were subsequently used to screen shared hub genes and predict TFs. In addition, gene set variation analysis (GSVA) and CIBERSORTx were used to calculate the correlations between hub genes and immune cells as well as related pathways. To confirm these results, hub genes and TFs were verified in microarray and single-cell RNA sequencing (scRNA-seq) datasets. Results: Following WGCNA and limma analysis, 152 shared genes were identified. These genes were involved in interferon (IFN) response and cytokine-mediated signaling pathway. Moreover, we screened six shared genes, namely IFI44L, ISG15, IFIT1, USP18, RSAD2 and ITGB2, out of which three genes, namely IFI44L, ISG15 and ITGB2 were found to be highly expressed in both microarray and scRNA-seq datasets. IFN response and ITGB2 signaling pathway were identified as potentially relevant pathways. In addition, STAT1 and IRF7 were identified as common TFs in both diseases. Conclusion: This study revealed IFI44L, ISG15 and ITGB2 as the shared genes and identified STAT1 and IRF7 as the common TFs of SLE and pSS. Notably, the IFN response and ITGB2 signaling pathway played vital roles in both diseases. Our study revealed common pathogenetic characteristics of SLE and pSS. The particular roles of these pivotal genes and mutually overlapping pathways may provide a basis for further mechanistic research.

Corrigendum: Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren's syndrome based on integrated bioinformatics and single-cell RNA-seq analysis.

[This corrects the article DOI: 10.3389/fimmu.2023.1212330.].

The Role of Cystathionine-ß-Synthase, H2S, and miRNA-377 in Hypoxic-Ischemic Encephalopathy: Insights from Human and Animal Studies.

We aimed to investigate the mechanism underlying the roles of miRNA-377, Cystathionine-ß-synthase (CBS), and hydrogen sulfide (H2S) in the development of hypoxic-ischemic encephalopathy (HIE). We investigated the relationship between CBS, H2S, and miR-377 in both humans with HIE and animals with hypoxic-ischemic insult. An animal model of fetal rats with hypoxic-ischemic brain injury was established, and the fetal rats were randomly assigned to control and hypoxic-ischemic groups for 15 min (mild) and 30 min (moderate) groups. Human samples were collected from children diagnosed with HIE. Healthy or non-neurological disease children were selected as the control group. Hematoxylin-eosin (HE) staining, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot were used to conduct this study. Hypoxia-ischemia induced pathological alterations in brain tissue changes were more severe in groups with severe hypoxic insult. miRNA-377 expression levels were upregulated in brain tissue and serum of fetal rats and human samples with HIE compared to controls. Conversely, CBS and H2S expression levels were significantly decreased in both human and animal samples compared to controls. Our findings suggest that CBS is a target gene of miR-377 which may contribute to the development of HIE by regulating CBS/H2S. H2S has a protective effect against hypoxic damage in brain tissue. The study provides new insights into the potential mechanisms underlying the protective role of H2S in hypoxic brain damage and may contribute to the development of novel therapies for HIE.

The relationship between miRNA-210 and SCN1B in fetal rats with hypoxic-ischemic brain injury.

Hypoxic-ischemic brain injury contributes to major neurodevelopmental disorders and is one of the leading causes of seizures, which substantially results in neurodevelopmental impairments with long-lasting outcomes and is one of the main causes of death in neonates. We aimed to investigate the correlation between miRNA-210 and SCN1B, a voltage-gated sodium channel gene, in brain tissue of fetal rats with hypoxic-ischemic brain injury. We found that after 10 min of hypoxia-ischemia, all reperfusion groups showed different degrees of damage. The degree of the injury increased in all the groups after 30 min of hypoxia-ischemia. Those changes include changes in the pericellular lumen, capillaries in the cortex, erythrocytes, enlarged pericellular lumen, the enlarged pericapillary lumen in the cortex, edema around glial cells, enlarged gap to form multiple necrotic foci, deformation of neurons, and loss of cell structure. The expression levels of HIF-1α, miRNA-210, and HIF-1α mRNA were higher in the hypoxic-ischemic groups than that in the control groups, among which the expression levels in the severe group were higher than that in mild group. SCN1B is down-regulated in both the mild and severe groups, and the lowest level was found at 30 min after hypoxia in both groups. MiRNA-210 plays a role in the development of hypoxic-ischemic encephalopathy (HIE) by regulating the expression changes of SCN1B. The brain tissue of fetal rats in the hypoxic-ischemic animal model showed pathological changes of brain injury.

Influence of Monocalcium Phosphate on the Properties of Bioactive Magnesium Phosphate Bone Cement for Bone Regeneration.

Bone defects occurring for various reasons can lead to deformities and dysfunctions of the human body. Considering the need for clinical applications, it is essential for bone regeneration to exploit a scaffold with bioactive bone cement. In this study, we fabricated bioactive magnesium phosphate bone cement (BMPC) at room temperature; then, it was set at to °C and 100% humidity for 2 h. The process was as follows: Simulating a clinical environment, magnesium oxide (MgO) was formed by calcining basic magnesium carbonate (Mg2(OH)2CO3). MgO, potassium dihydrogen phosphate (KH2PO4) and carboxymethyl chitosan (C20H37N3O14, CMC) were mixed to form magnesium phosphate bone cement (MPC); then, monocalcium phosphate (Ca(H2PO4)2) was added to neutralize the alkaline product after MPC hydration to fabricate bioactive magnesium phosphate bone cement (BMPC). The influence of the doped content of Ca(H2PO4)2 on the properties of bone cement was discussed. The results showed that Ca(H2PO4)2 and CMC can adjust the setting time of bone cement to between 8 and 25 min. The compressive strength increased first and then decreased. After 48 h without additional pressure, the compressive strength reached the maximum value, which was about 38.6 MPa. Ca(H2PO4)2 and CMC can play a synergistic role in regulating the properties of BMPC. The BMPC was degradable in the simulated body fluid (SBF). The results of the cytotoxicity experiment and laser confocal microscopy experiment indicated that BMPC fabricated at room temperature had better biocompatibility and degradability, which was more consistent with clinical operation requirements. BMPC is a promising orthopedic material and is suitable for repairing bone defects.

Experimental Study on the Correlation between miRNA-373 and HIF-1α, MMP-9, and VEGF in the Development of HIE.

INTRODUCTION: Microribonucleic acids (miRNAs) have short (approximately 18 to 25) nucleotides and are evolutionarily conserved and endogenously expressed RNAs belonging to a family of noncoding RNA molecules. miRNA-373 regulates cell proliferation, migration, apoptosis, invasion, and repairing damaged DNA after hypoxia stress. Neonatal hypoxic-ischemic encephalopathy (HIE) refers to perinatal asphyxia caused by partial or complete hypoxia, reduced or suspended cerebral blood flow, and fetal or neonatal brain damage. We aim to investigate the relationship between miRNA-373 and HIF-1α, between miRNA-373 MMP-9, and between miRNA-373 VEGF in the occurrence and development of HIE. METHODS: Human (children) samples were divided into four groups (n = 15 in each group) according to HIE severity. The patient group was divided into middle, moderate, and severe HIE groups. The control group included healthy children or children with nonneurological diseases. The expressions of miRNA-373, HIF-1α, MMP-9, and VEGF were assayed in the serum samples. RESULTS: Our study showed a strong relationship between miRNA-373 and HIF-1α, between miRNA-373 and MMP-9, and between miRNA-373 and VEGF. The expression levels of miRNA-373, HIF-1α, MMP-9, and VEGF in the HIE groups were much higher than those of the control group. CONCLUSION: The increased change in miRNA-373 expression has a certain diagnostic significance on neonatal HIE. In the occurrence and development of HIE, miRNA-373 is positively correlated with HIF-1α, MMP-9, and VEGF.

Effect and Mechanism of Ganoderma lucidum Spores on Alleviation of Diabetic Cardiomyopathy in a Pilot in vivo Study.

BACKGROUND: Ganoderma lucidum spores (GLS) exhibit disease prevention properties, but no study has been carried out on the anti-diabetic cardiomyopathy property of GLS. The aim of this study was to evaluate the hyperglycemia-mediated cardiomyopathy protection and mechanisms of GLS in streptozotocin (STZ)induced diabetic rats. METHODS: Male SD rats were randomly divided into three groups. Two groups were given STZ (50 mg/kg, i.p.) treatment and when their fasting plasma glucose was above 16.7 mmol/L, among them, one group was given placebo, as diabetic group, and another group was given GLS (300 mg/kg) treatment. The group without STZ treatment was given placebo as a control group. The experiment lasted 70 days. The histology of myocardium and biomarkers of antioxidants, myocardial injury, pro-inflammatory cytokines, pro-apoptotic proteins and phosphorylation of key proteins in PI3K/AKT pathway were assessed. RESULTS: Biochemical analysis showed that GLS treatment significantly reduced the blood glucose (-20.3%) and triglyceride (-20.4%) levels compared to diabetic group without treatment. GLS treatment decreased the content of MDA (-25.6%) and activity of lactate dehydrogenase (-18.9%) but increased the activity of GSH-Px (65.4%). Western blot analysis showed that GLS treatment reduced the expression of both alpha-smooth muscle actin and brain natriuretic peptide. Histological analysis on the cardiac tissue micrographs showed that GLS treatment reduced collagen fibrosis and glycogen reactivity in myocardium. Both Western blot and immunohistochemistry analyses showed that GLS treatment decreased the expression levels of pro-inflammatory factors (cytokines IL-1ß, and TNF-α) as well as apoptosis regulatory proteins (Bax, caspase-3 and -9), but increased Bcl-2. Moreover, GLS treatment significantly increased the phosphorylation of key proteins involved in PI3K/AKT pathway, eg, p-AKT p-PI3K and mTOR. CONCLUSION: The results indicated that GLS treatment alleviates diabetic cardiomyopathy by reducing hyperglycemia, oxidative stress, inflammation, apoptosis and further attenuating the fibrosis and myocardial dysfunction induced by STZ through stimulation of the PI3K/Akt/mTOR signaling pathway.

Associated Targets of the Antioxidant Cardioprotection of Ganoderma lucidum in Diabetic Cardiomyopathy by Using Open Targets Platform: A Systematic Review.

Even with substantial advances in cardiovascular therapy, the morbidity and mortality rates of diabetic cardiomyopathy (DCM) continually increase. Hence, a feasible therapeutic approach is urgently needed. Objectives. This work is aimed at systemically reviewing literature and addressing cell targets in DCM through the possible cardioprotection of G. lucidum through its antioxidant effects by using the Open Targets Platform (OTP) website. Methods. The OTP website version of 19.11 was accessed in December 2019 to identify the studies in DCM involving G. lucidum. Results. Among the 157 cell targets associated with DCM, the mammalian target of rapamycin (mTOR) was shared by all evidence, drug, and text mining data with 0.08 score association. mTOR also had the highest score association 0.1 with autophagy in DCM. Among the 1731 studies of indexed PubMed articles on G. lucidum published between 1985 and 2019, 33 addressed the antioxidant effects of G. lucidum and its molecular signal pathways involving oxidative stress and therefore were included in the current work. Conclusion. mTOR is one of the targets by DCM and can be inhibited by the antioxidative properties of G. lucidum directly via scavenging radicals and indirectly via modulating mTOR signal pathways such as Wnt signaling pathway, Erk1/2 signaling, and NF-κB pathways.