Journal of Bioenergetics and Biomembranes最新文献

Cardiovascular diseases (CVDs) are the leading cause of death globally, attributed to a complex etiology involving metabolic, genetic, and protein-related factors. Lipoprotein(a) (Lp(a)), identified as a genetic risk factor, exhibits elevated levels linked to an increased risk of cardiovascular diseases. The lipoprotein(a) kringle domains have recently been identified as a potential target for the treatment of CVDs, in this study we utilized a fragment-based drug design approach to design a novel, potent, and safe inhibitor for lipoprotein(a) kringle domain. With the use of fragment library (61,600 fragments) screening, combined with analyses such as MM/GBSA, molecular dynamics simulation (MD), and principal component analysis, we successfully identified molecules effective against the kringle domains of Lipoprotein(a). The hybridization process (Breed) of the best fragments generated a novel 249 hybrid molecules, among them 77 exhibiting superior binding affinity (≤ -7 kcal/mol) compared to control AZ-02 (-6.9 kcal/mol), Importantly, the top ten molecules displayed high similarity to the control AZ-02. Among the top ten molecules, BR1 exhibited the best docking energy (-11.85 kcal/mol ), and higher stability within the protein LBS site, demonstrating the capability to counteract the pathophysiological effects of lipoprotein(a) [Lp(a)]. Additionally, principal component analysis (PCA) highlighted a similar trend of motion during the binding of BR1 and the control compound (AZ-02), limiting protein mobility and reducing conformational space. Moreover, ADMET analysis indicated favorable drug-like properties, with BR1 showing minimal violations of Lipinski’s rules. Overall, the identified compounds hold promise as potential therapeutics, addressing a critical need in cardiovascular medicine. Further preclinical and clinical evaluations are needed to validate their efficacy and safety, potentially ushering in a new era of targeted therapies for CVDs.

Circular RNAs (circRNAs) showing unusual expressions have been discovered in pancreatic adenocarcinoma (PAAD). However, the functions and underlying mechanisms of these circRNAs still remain largely unclear. Our current study discovered a notable increase in the expression of circRNA hsa_circ_0002395 (circ_0002395) in both PAAD tissues and cell lines. This up-regulation of circ_0002395 was found to be associated with larger tumor sizes and lymph node metastasis. Furthermore, our findings showed that circ_0002395 facilitated aerobic glycolysis and cell proliferation in PAAD cells by regulating the miR-548c-3p/PDK1 axis. Mechanistically, we identified circ_0002395 as a competing endogenous RNA (ceRNA) that sponged miR-548c-3p, thereby promoting PDK1 expression and aerobic glycolysis, and ultimately resulting in the enhancement of cell proliferation. Our findings found that circ_0002395 promoted proliferation of PAAD cells by enhancing PDK1 expression and aerobic glycolysis by sponging miR-548c-3p.

White matter injury (WMI) resulting from intracerebral hemorrhage (ICH) is closely associated with adverse prognoses in ICH patients. Although Circ-AGTPBP1 has been reported to exhibit high expression in the serum of premature infants with WMI, its effects and mechanisms in ICH-induced WMI remain unclear. This study aimed to investigate the role of circ-AGTPBP1 in white matter injury after intracerebral hemorrhage. An intracerebral hemorrhage rat model was established by injecting autologous blood into rat left ventricles and circ-AGTPBP1 was knocked down at the ICH site using recombinant adeno-associated virus, AAV2/9. Magnetic resonance imaging (MRI) and gait analysis were conducted to assess long-term neurobehavioral effects. Primary oligodendrocyte progenitor cells (OPCs) were isolated from rats and overexpressed with circ-AGTPBP1. Downstream targets of circ-AGTPBP1 in OPCs were investigated using CircInteractome, qPCR, FISH analysis, and miRDB network. Luciferase gene assay was utilized to explore the relationship between miR-140-3p and Pcdh17 in OPCs and HEK-293T cells. Finally, CCK-8 assay, EdU staining, and flow cytometry were employed to evaluate the effects of mi-RNA-140-3p inhibitor or silencing of sh-pcd17 on the viability, proliferation, and apoptosis of OPCs. Low expression of circ-AGTPBP1 alleviates white matter injury and improves neurological functions in rats after intracerebral hemorrhage. Conversely, overexpression of circ-AGTPBP1 reduces the proliferative and migrative potential of oligodendrocyte progenitor cells and promotes apoptosis. CircInteractome web tool and qPCR confirmed that circ-AGTPBP1 binds with miR-140-3p in OPCs. Additionally, miRDB network predicted Pcdh17 as a downstream target of miR-140-3p. Moreover, pcdh17 expression was increased in the brain tissue of rats with intracerebral-induced white matter injury. Furthermore, inhibiting miR-140-3p suppressed the proliferation and migration of OPCs and facilitated apoptosis through Pcdh17. Circ-AGTPBP1 promotes white matter injury through modulating the miR-140-3p/Pcdh17 axis. The study provides a new direction for developing therapeutic strategies for white matter injury.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. The mechanism by which medium- and long-chain triglyceride (MCT/LCT) propofol plays a role in promoting NAFLD remains unclear. In this study, we investigated the effect of MCT/LCT propofol on NAFLD progression and its mechanism of action. In Huh-7 and HepG3 cells induced by free fatty acids (FFA), propofol downregulated the expression levels of TG and lipid metabolism-related proteins by promoting the activation of the PI3K/AKT pathway and suppressing FFA-induced lipid metabolic disorders. In a high-fat diet (HFD) -induced NAFLD mouse model, we demonstrated that propofol significantly inhibited liver steatosis, inflammatory cell infiltration, and fibrosis. In conclusion, our results suggest that MCT/LCT propofol reduces liver lipid accumulation by activating the PI3K/AKT pathway and further suppressing the NAFLD process.

Chondrocyte ferroptosis constitutes a major cause of the development of osteoarthritis (OA). Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have a protective role against ferroptosis in various diseases. Hence, we aimed to determine whether BMSC-Exos alleviated chondrocyte ferroptosis and its effect on OA, and to dissect out the possible mechanisms. An OA rat chondrocyte model was established by interleukin-1β (IL-1β) exposure, and treated with BMSC-Exos/ferroptosis inhibitor Ferrostatin-1. Cell viability/ferroptosis-related index levels [reactive oxygen species (ROS)/malondialdehyde (MDA)/glutathione (GSH)]/cell death/ACSL4 mRNA and protein levels and METTL3 levels were assessed by MTT/kits/immunohistochemical method and TUNEL staining/RT-qPCR and Western blot. METTL3/ACSL4 were overexpressed in rat chondrocytes to evaluate their role in BMSC-Exo-produced repression on chondrocyte ferroptosis. Bioinformatics website predicted the presence of m6A modification sites on ACSL4 mRNA, with the m6A level enriched on it assessed by MeRIP/RT-qPCR. ACSL4 mRNA stability was detected by actinomycin D assay. A surgical destabilized medial meniscus rat OA model was also established, followed by injection with BMSC-Exos to verify their function. IL-1β stimulation in rat chondrocytes inhibited cell viability, elevated Fe²⁺/ROS/MDA levels, declined GSH levels and increased TUNEL positive cell number and ACSL4 level, which were neutralized by BMSC-Exos. BMSC-Exos limited chondrocyte ferroptosis by down-regulating METTL3, with the effect abrogated by METTL3 overexpression. METTL3 regulated the m6A modification of ACSL4 mRNA, increasing ACSL4 mRNA stability and ACSL4 expression. BMSC-Exos reduced chondrocyte ferroptosis and prevented OA progression via disruption of the METTL3-m6A-ACSL4 axis. BMSC-Exos might exert a chondroprotective effect by attenuating chondrocyte ferroptosis and alleviate OA progression.

Circular RNA (circRNA) plays multiple roles in the development of esophageal cancer (EC). Herein, we investigate the function of circ_0001944 in EC progression and the related mechanism. Expression of circ_0001944, microRNA-338-5p (miR-338-5p), pyruvate dehydrogenase kinase 1 (PDK1), E-cadherin and N-cadherin was analyzed by quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry assay. Cell viability, proliferation, apoptosis, invasion and migration were investigated by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell invasion and wound-healing assays, respectively. Glucose consumption was detected by Glucose Assay Kit. Lactate production was analyzed by Lactate Assay Kit. ATP/ADP ratio was determined by ADP/ATP ratio Assay Kit. The associations among circ_0001944, miR-338-5p and PDK1 were identified by dual-luciferase reporter and RNA pull-down assays. Xenograft mouse model assay was used to explore the role of circ_0001944 on tumor tumorigenesis in vivo. Circ_0001944 and PDK1 expression were significantly upregulated, while miR-338-5p was downregulated in EC tissues and cells in contrast with normal esophageal tissues and cells. Circ_0001944 knockdown inhibited EC cell proliferation, invasion, migration and glycolysis but induced apoptosis. Meanwhile, circ_0001944 depletion suppressed tumor tumorigenesis in vivo. Mechanistically, circ_0001944 bound to miR-338-5p, and miR-338-5p targeted PDK1. In addition, miR-338-5p inhibitors attenuated circ_0001944 depletion-induced effects in EC cells. The regulation of miR-338-5p on EC progression involved the downregulation of PDK1. Further, circ_0001944 controlled PDK1 expression through miR-338-5p. Circ_0001944 knockdown inhibited EC development and glycolysis by regulating the miR-338-5p/PDK1 pathway, providing a promising target for EC therapy.

To verify the protective effect of circDNAJB6 on Bronchopulmonary dysplasia (BPD) cell and animal models and to explore the possible mechanism of its protective effect. The function of circDNAJB6 was investigated at the cell and animal levels. Nuclear and Cytoplasmic RNA extraction kits and fluorescence in situ hybridization (FISH) were used to explore the distribution of circDNAJB6 in cells, and the potential mechanism of circDNAJB6 was verified by q-PCR, luciferase assays and rescue experiments.CircDNAJB6 is abundant in breast milk exosomes. Overexpression of circDNAJB6 can ameliorate damage in BPD models caused by hyperoxia exposure in vivo and in vitro. Mechanistically, circDNAJB6 can target the downstream DNAJB6 gene and promote the transcription of DNAJB6, exertive a protective effect on the experimental BPD model. Our results showed that circDNAJB6 alleviated damage and inhibited the proliferation of alveolar epithelial cells in the BPD model by promoting transcription of parent gene DNAJB6. Human milk exosome-derived circDNAJB6 provides new directions for preventing and treating BPD.

Background

This study aimed to investigate the role of circSlc8a1 in cardiac hypertrophy (CH), a pathological change in various cardiovascular diseases.

Methods

An in vitro CH model was established using angiotensin II (AngII) treated H9c2 cells, followed by western blotting and RT-qPCR for detecting relative expressions. Cell viability and proliferation were analyzed using CCK-8 and EdU assays, while lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH), and iron levels were determined using corresponding kits. Moreover, dual-luciferase reporter and RNA pull-down assays were performed to demonstrate whether miR-673-5p is bound to circSlc8a1 or transferrin receptor (TFRC).

Results

The results indicated that the expressions of circSlc8a1 and TFRC were increased, while miR-673-5p was decreased in the AngII treated H9c2 cells. The ferroptosis inhibitor treatment decreased the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-major histocompatibility complex (β-MHC) protein expressions, and circSlc8a1 expressions. Knocking down of circSlc8a1 inhibited promoted the cell viability and proliferation, increased the GSH content, glutathione peroxidase 4, and solute carrier family 7 member 11 protein expressions, and decreased the LDH, ROS, iron levels, and RAS protein expressions. The MiR-673-5p inhibitor antagonized the role of si-circSlc8a1, and the over-expressed TFRC reversed the miR-673-5p mimicking effects in AngII treated H9c2 cells.

Conclusion

CircSlc8a1 promoted the ferroptosis in CH via regulating the miR-673-5p/TFRC axis.

Herein, PC12 cells were applied to detect the impact of progesterone under oxygen glucose deprivation/reperfusion (OGD/R) stimulation. The cell proliferation of PC12 cells was evaluated by cell counting kit-8 assay, and the concentrations of MDA, ROS and SOD were examined by their corresponding Enzyme Linked Immunosorbent Assay kits. The invasion and migration properties of PC12 cells were evaluated by transwell and wound healing assays, respectively. The expression patterns of related genes were evaluated by western blot and qPCR. Under OGD/R stimulation, progesterone treatment could elevate the viability of PC12 cells, reduce the levels of MDA and ROS, and elevate the concentration of SOD. Moreover, progesterone treatment could strengthen the invasion and migration abilities of PC12 cells under OGD/R condition, as well as decrease the apoptosis and inflammation. FABP5 expression was significantly increased in PC12 cells under OGD/R stimulation, which was reversed after progesterone stimulation. Under OGD/R stimulation, the protective effects of progesterone on PC12 cells were strengthened after si-FABP5 treatment. The protein levels of TLR4, p-P65 NF-κB, and P65 NF-κB in OGD/R-induced PC12 cells were increased, which were inhibited after progesterone treatment. Progesterone exerted protective effects on PC12 cells by targeting FABP5 under OGD/R stimulation.

Viruses are microscopic biological entities that can quickly invade and multiply in a living organism. Each year, over 36,000 people die and nearly 400 million are infected with the dengue virus (DENV). Despite dengue being an endemic disease, no targeted and effective antiviral peptide resource is available against the dengue species. Antiviral peptides (AVPs) have shown tremendous ability to fight against different viruses. Accelerating antiviral drug discovery is crucial, particularly for RNA viruses. DDX3X, a vital cell component, supports viral translation and interacts with TRPV4, regulating viral RNA metabolism and infectivity. Its diverse signaling pathway makes it a potential therapeutic target. Our study focuses on inhibiting viral RNA translation by blocking the activity of the target gene and the TRPV4-mediated Ca²⁺ cation channel. Six major proteins from camel milk were first extracted and split with the enzyme pepsin. The antiviral properties were then analyzed using online bioinformatics programs, including AVPpred, Meta-iAVP, AMPfun, and ENNAVIA. The stability of the complex was assessed using MD simulation, MM/GBSA, and principal component analysis. Cytotoxicity evaluations were conducted using COPid and ToxinPred. The top ten AVPs, determined by optimal scores, were selected and saved for docking studies with the GalaxyPepDock tools. Bioinformatics analyses revealed that the peptides had very short hydrogen bond distances (1.8 to 3.6 Å) near the active site of the target protein. Approximately 76% of the peptide residues were 5–11 amino acids long. Additionally, the identified peptide candidates exhibited desirable properties for potential therapeutic agents, including a net positive charge, moderate toxicity, hydrophilicity, and selectivity. In conclusion, this computational study provides promising insights for discovering peptide-based therapeutic agents against DENV.