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Identifying Potent 9-Anilinoacridine-Based HER2 Breast Cancer Inhibitors Using in Silico Computational Approaches
No full textBackground: Because of their anti-proliferative effects, 9-anilinoacridines are important as antitumor agents with DNA-intercalating properties. In this study, anticancer drugs with 9-anilinoacridines, such as amascrine and nitracrine, were developed. Pharmacophore modelling, molecular docking, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), induced fit docking and a molecular dynamics (MD) study were performed to investigate the binding affinity of 9-anilinoacridines with heterocyclic substitutes as selective human epidermal growth factor receptor 2 (HER2) inhibitors for breast carcinoma. Methods: The pharmacophore model was developed using the Schrödinger suite 2019-2 phase module. 3D structures of dataset compounds were generated using Maestro version 9.6 and optimised using the LigPrep design of the Schrödinger suite 2019-2. To predict the binding free energy of the ligands in the complex with Protein Data Bank (pdb), we performed post-docked energy minimisation using the Prime MM-GBSA module. Induced fit docking studies were performed to determine the ligand-modulated dynamic behaviour shown in the protein MD study. Using the Desmond module in Schrödinger 2019-2, the complex in the optimized potentials for liquid simulations 3 (OPLS3) force fields explicit solvent system was investigated. Using the pharmacophore hypothesis, a statistically substantial 3 Dimensional Quantitative Structure Activity Relationship (3D-QSAR) design was created. Results: We obtained the top five hypotheses, and according to the scoring parameters, the best model was identified as the 3D-QSAR model A-Acceptor, D-Donar, R-Ring (model AADRRR)-21. From the contour map analysis, we found that the presence of a hydrogen-bond donor and electron-withdrawing and hydrophobic features are crucial for inhibiting the HER2 enzyme. The docking study showed that the ligands have significant G-score (Glide Score) values from –4.18 to –9.96 kcal/mol. A 15-ns MD simulation was also run to determine the molecular details involving the affinity of 3m in active site 3PP0.pdb. The binding free energy was determined using the Prime MM-GBSA module, and dG binding values were observed from –35.11 to –106.87 kcal/mol. Conclusions: We designed and developed a pharmacophore hypothesis and 3D-QSAR model and then elucidated the structural features and spatial arrangement of atoms responsible for the HER2 inhibitory activity of 9-anilinoacridines. The predicted 3D-QSAR model significantly correlated with experimentally reported in vitro antitumor activity. The findings indicated that additional pharmacophore feature modifications might enhance the HER2 inhibitory activity of 9-anilinoacridines
Immature Granulocytes are Closely Associated with the Development of Maternal Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes
Get PDFBackground: Gestational diabetes mellitus (GDM) is defined as any degree of dysglycaemia that occurs for the first time or is first detected during pregnancy. GDM causes various complications for both the mother and fetus. Immature granulocytes (IGs) may enter the peripheral blood in response to infection, inflammation, or other stimuli. In this study, we delve into the role of IGs in the occurrence and development of GDM as well as their correlation with pregnancy outcomes. Purpose: This study aimed to investigate the risk factors for gestational diabetes mellitus (GDM) as well as the correlation between immature granulocytes (IGs) and maternal pregnancy outcome. Methods: This study was conducted between January 1, 2019 and December 31, 2019 at the Womens Hospital, School of Medicine, Zhejiang University. We collected maternal demographic data and clinical information on major adverse pregnancy outcomes from medical records. We implemented multiple logistic regression models to determine the association between maternal IGs and adverse pregnancy outcomes. Results: A total of 9558 pregnant women, including 7613 controls (those without GDM) and 1945 pregnant women diagnosed with GDM. We found that compared to those without GDM (control group), GDM patients exhibited a significantly higher percentage of immature granulocytes (1.22% ± 1.03% vs. 1.34% ± 1.26%, p < 0.01), and absolute immature granulocyte count (0.12 ± 0.13 × 109/L vs. 0.14 ± 0.15 × 109/L, p < 0.001). Furthermore, GDM patients manifested substantially higher rates of premature birth (6.96% vs. 10.13%, p < 0.001), macrosomia (4.39% vs. 5.55%, p < 0.05), and cesarean section (34.6% vs. 41.8%, p < 0.001). We found that after adjusting for potential confounding variables, IGs were found to be associated with a high risk for GDM (absolute value of IGs, adjusted odds ratio [aOR] = 2.265; percentage of IGs [aOR = 1.100]), preterm birth (absolute value of IGs, aOR = 5.325; percentage of IGs, aOR = 1.209), and macrosomia (absolute IG count, aOR = 1.503). Conclusions: Our study demonstrates an association between IGs and GDM. Furthermore, IGs can serve as a risk factor associated with preterm delivery and macrosomia
m6Am Methyltransferase Pcif1 Knockdown Attenuates Mouse Cerebral Ischemia-Reperfusion Injury in Vitro through Inhibiting Pdpk1 mRNA Translation
No full textBackground: Ischemia-reperfusion (I/R) injury is a key challenge in the treatment of ischemic cerebrovascular diseases. This study aimed to explore whether phosphorylated C-terminal domain (CTD) interacting factor 1 (Pcif1) could attenuate mouse I/R injury and its downstream mechanisms. Methods: An I/R injury cellular model was induced by treating mouse cortical neurons with oxygen-glucose deprivation and reoxygenation (OGD/R). Mouse cortical neurons were normally cultured (control group cells), and all were subjected to OGD/R after transfection. These were categorized into various groups, including OGD/R group (OGD/R model cells), OGD/R+siRNA negative control (siNC) group (cells were transfected with siNC and then underwent OGD/R treatment), OGD/R+siPcif1-1/2/3 group (OGD/R cells were transfected with siPcif1-1/2/3 before OGD/R treatment), siNC+shNC group (siNC and shNC were transfected into cells), siNC+3-phosphoinositide-dependent protein kinase 1 (Pdpk1) short hairpin RNA (shPdpk1) group (siNC and shPdpk1 were transfected into cells), siPcif1+shNC group (cells were transfected with siPcif1 and shNC), and siPcif1+shPdpk1 group (cells were transfected with siPcif1 and shPdpk1). Pcif1 and Pdpk1 expressions were detected by quantitative real-time PCR. The effects of silenced Pcif1 on cell viability, lactate dehydrogenase (LDH) release rate, malondialdehyde (MDA) level, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) concentrations, apoptosis, and V-akt murine thymoma viral oncogene homolog (Akt) related proteins were evaluated by cell counting kit-8 assay, LDH activity assay kit, MDA assay kit, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blot, respectively. The targeting relationship between Pcif1 and Pdpk1 was analyzed by m6A-RNA immunoprecipitation qPCR. The loss-of-function assays were used to evaluate the function of Pdpk1 knockdown on OGD/R-treated cells. Results: Pcif1 expression was elevated but Pdpk1 expression was reduced in mouse cortical neurons following OGD/R treatment (p < 0.001). Pcif1 silencing reversed the effects of OGD/R treatment on inhibiting cell viability, and on promoting LDH release, MDA level, TNF-α, and IL-6 contents and apoptosis rate (p < 0.001). Pcif1 knockdown also facilitated B-cell chronic lymphocytic leukemia/lymphoma-2 (Bcl-2) expression and Akt signaling pathway activation, and suppressed Bcl-2-associated X protein (Bax) expression (p < 0.05). Pdpk1 was validated as a downstream target of Pcif1, and its knockdown offset the above effects induced by silencing Pcif1 on OGD/R-treated cells (p < 0.05). Conclusions: Pcif1 knockdown alleviates OGD/R-induced neuronal injury in mice by inhibiting Pdpk1 mRNA translation to activate Akt signaling pathway
Validation of OnePGT in Preimplantation Genetic Testing
No full textBackground: Chromosomal abnormalities, such as changes in ploidy, aneuploidy, and structural changes, as well as duplication and deletion of microfragments, contribute to reduced implantation rate, pregnancy loss, and congenital disabilities in humans. In this study, we explored the significance of One preimplantation genetic testing (OnePGT) in preimplantation genetic testing (PGT). Methods: In this study, 20 embryos representing seven families undergoing PGT for monogenic disorders (PGT-M) and 11 embryos representing five families undergoing PGT for chromosomal structural rearrangements (PGT-SR) were selected for re-biopsy at our Reproductive Medicine Center. Moreover, blood samples were also obtained from the parents. For monogenic disease (MGD) analysis, 20 embryo samples (7 controls) and parental DNA samples were amplified. A whole-genome library was built and subsequently sequenced to obtain Single Nucleotide Polymorphism (SNP) data of ±2 Mb of the control embryo pathogenic gene loci and SNP data of parental samples. Furthermore, the embryos were screened for carrying any pathogenic gene loci, and the feasibility and accuracy of the OnePGT method relative to the original results in detecting MGDs were analyzed. However, in chromosomal structural rearrangement testing, 11 embryos (4 controls) and parental DNA samples were amplified, and the SNP data of ±2 Mb of chromosomal structural abnormalities were compared to differentiate the carrier embryo from normal ones. Additionally, the aforementioned embryo samples were analyzed for aneuploidy detection, and the accuracy of the aneuploidy detection through OnePGT was compared with the original results, as well as the degree of chimera coincidence. Results: The genetic results of embryos in patients with three MGDs (α-thalassemia, β-thalassemia, and spinal muscular atrophy), reciprocal chromosomal translocation, and Robertsonian translocation detected by the OnePGT method were consistent with those detected by the conventional method. Furthermore, compared to findings from the conventional method, OnePGT exhibited a 100% coincidence rate in distinguishing chromosomal translocation carrying embryos from normal, a 72% coincidence rate in the detection of aneuploidy, and a 50% coincidence rate in chimera. Conclusions: OnePGT is a novel, comprehensive, and effective three-in-one detection method for PGT
NAC Mitigates ROS Accumulation and NLRP3 Inflammasome-Related Expression and Attenuates Vascular Pyrosis in Intracranial Aneurysms
No full textBackground: Tissues surrounding ruptured aneurysms exhibit heightened inflammatory activation. Oxidative stress is a pivotal factor in endothelial injury, where moderate and high concentrations of reactive oxygen species induce apoptosis via oxidative stress. Furthermore, oxidative stress and reactive oxygen species have been implicated in vascular smooth muscle cells (VSMC) phenotypic switch and apoptosis. This study aimed to investigate the impact of N-acetyl-L-cysteine (NAC) in a rat aneurysm model subjected to a high salt diet and surgical intervention. Methods: Rats were randomly divided into four groups: normal control, surgery alone, surgery with low-dose NAC, and surgery with high-dose NAC. A cerebral aneurysm model was induced in the latter three groups by ligating the posterior branches of bilateral renal arteries and the left common carotid artery and administering a high salt (8% NaCl) diet for 3 months. The control group received a high salt (8% NaCl) diet only. Inflammatory factor levels were assessed using enzyme-linked immunosorbent assay (ELISA), and related protein expression was examined via western blot. Results: Treatment with NAC significantly delayed the progression of cerebral aneurysms, exerting an inhibitory effect on inflammation. Expression levels of nucleotide-binding oligomerization domain, leucine-rich repeats and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speckled protein (ASC), Caspase-1, interleukin-6 (IL-6), and tumor necrosis factor (TNF) proteins in cerebral aneurysm tissues were markedly reduced. NAC treatment led to a significant decrease in reactive oxygen species (ROS) levels, particularly in the high-dose group. Transmission electron microscopy of the ultrastructure of the cells in each group revealed that cells in the aneurysms of the model group were charred and dead, while those in the arterial tissues of the NAC group exhibited intact nuclei and cytoplasm with rounded edges. Conclusion: NAC can diminish ROS production in cerebral aneurysm model rats, attenuating the oxidative stress and inflammatory response in cerebral aneurysms. This effect contributes to the reduction and delayed onset of cerebral aneurysms, ultimately improving the prognosis of cerebral aneurysms. Additionally, NAC may partially inhibit the expression process induced by ROS-mediated NLRP3 inflammasome
Establishing a Novel Qualitative Model to Predict Chemotherapy Response and Prognosis in Ovarian Cancer
No full textBackground: Ovarian cancer is frequently associated with chemoresistance, which is the major cause of treatment failure. In this study, we utilized relative expression ordering (REO) of gene pairs to develop a novel model to predict chemotherapy response and prognosis in ovarian cancer. Moreover, we attempted to explore the mechanisms underlying ovarian cancer chemoresistance. Methods: Datasets were downloaded from publicly available databases, and differentially expressed gene pairs were filtered using Wilcoxon signed-rank test, Cox proportional hazards regression and Fishers test to develop the model. Subsequently, the efficacy was validated by Kaplan–Meier analysis in training and validation sets. Comprehensive investigations were performed to investigate pathway variation, immune infiltration, and single-cell analysis. Next, gene expression was measured in chemoresistant ovarian cancer cells and their parent cells, and risk scores were calculated. Finally, a series of experiments were conducted to evaluate the regulatory impacts on chemosensitivity of lysyl oxidase-like 4 (LOXL4), one of the upregulated genes in chemoresistant cells. Results: The developed model, comprising 19 genes for predicting chemoresistance and prognosis, demonstrated robust performance in training and five validation sets. Chemoresistant samples identified by this model exhibited enrichment of genes in four pathways and downregulation of genes in one pathway. Besides, chemoresistant samples displayed a lower abundance of various immune cell types, indicating immune suppression within the tumor microenvironment. Single-cell analysis indicated heterogeneity within samples, revealing cell populations that may survive after chemotherapy. Chemoresistant ovarian cells exhibited higher risk scores compared to their parent cells, and LOXL4 was found to modulate cisplatin sensitivity in ovarian cancer cells. Conclusions: This study presents a novel prognostic model and provides possible therapeutic targets for further research in ovarian cancer
Targeting TRAF7 to Enhance Angiogenesis and Mitigate Ischemia-Induced Brain Damage: Insights from in Vivo and in Vitro Models
No full textBackground: Cerebral ischemic stroke (CIS) results from insufficient blood supply to the brain, leading to disabilities and even death. Currently, available CIS treatment primarily focuses on promoting angiogenesis. The tumor necrosis factor receptor-associated factor 7 (TRAF7) plays a pivotal role in various biological processes and has been associated with neuronal damage. However, its role in CIS remains uncertain. Therefore, this study aimed to investigate the role of TRAF7 in angiogenesis during CIS. Methods: A middle cerebral-arterial occlusion (MCAO) mice model with knocked-down TRAF7 was established to investigate its effects on neurological deficits, brain water content, and infarct volume. CD31/ki67 dual-immunofluorescent (IF) staining was performed to assess the impact of TRAF7 on angiogenesis in vivo. Furthermore, an Oxygen and Glucose Deprivation and Reoxygenation (OGD/R) cell model was constructed to mimic ischemia and explore the influence of the TRAF7/Krupple-like family of transcription factor 4 (KLF4) axis on cell migration and tube formation. Results: TRAF7 protein expression was found to be elevated in both the in vivo and in vitro ischemic models. Its silencing improved neurological function, reduced cerebral water content and infarct volume, and enhanced angiogenesis after CIS in vivo. Furthermore, its silencing promoted bEnd3 cell migration and tube formation following OGD/R injury. Moreover, it was observed that TRAF7 regulated expression levels of KLF4 and vascular endothelial growth factor (VEGF) in both in vivo and in vitro settings. Mechanistically, it was found that TRAF7 mediated bEnd3 cell migration and angiogenesis post-OGD/R injury by modulating KLF4 expression. Conclusions: Our findings indicate that TRAF7 knockdown confers vascular protection against CIS, offering a novel perspective for CIS treatment
Activity of the KRAS G12D Inhibitor MRTX1133 against the Mutant KRAS Triple-Negative MDA-MB-231 Breast Cancer Cell Line
No full textBackground: Although <2% of breast cancers exhibit Kirsten rat sarcoma virus (KRAS) mutations, KRAS activity plays a role in triple-negative breast cancer (TNBC)/basal-like tumors. TNBC accounts for approximately 15% of breast tumors and is associated with a poor prognosis. Mutant KRAS G12D-triggered activation of the Rat sarcoma virus-Mitogen activated protein kinase (RAS-MAPK) pathway promotes immune evasion in TNBC by remodeling the tumor immune microenvironment (TIME). Specifically, CD11b+ myeloid suppressor cells promote KRAS G12D-driven cancer and enhance the infiltration of CD4+Gata3+ Th2 regulatory T cells. Of the breast cancer cell lines, only MDA-MB231 cells carry the KRAS G13D mutation. In this study, the efficacy of the KRAS G12D inhibitor MRTX1133 in inhibiting KRAS-driven growth and the migration of the MDA-MB-231 cell line was evaluated. Methods: The proliferation, chemosensitivity and migration of the MDA-MB-231 KRAS G13D cell line in response to MRTX1133 was compared with those of the MDA-MB-436 KRAS wildtype cell line using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assays and scratch assays. Furthermore, phosphorylation of cellular proteins and alterations in protein expression in response to KRAS/Son of Sevenless 1 (SOS1) inhibitors was detected using protein profiler western blot arrays. Results: MRTX1133 significantly inhibited (p < 0.05) the proliferation of MDA-MB-231 cells but not that of MDA-MB-436 cells. Similarly, migration of MDA-MB-231 but not that of MDA-MB-436 was retarded by this inhibitor. Furthermore, the SOS1 inhibitors BAY-293, BI-3406 and MRTX0902 exhibited high antiproliferative activity against MDA-MB-231 cells. In case of lung cancer, MRTX1133 was highly active against the BH1194 KRAS G12D Non-small cell lung cancer (NSCLC) cell line but demonstrated low activity against the BH1338 KRAS G13D NSCLC cell line. In phosphoprotein arrays, the phosphorylation of Extracellular signal-Regulated Kinases 1/2 (ERK 1/2), cAMP-response Element Binding protein (CREB), Glycogen Synthase Kinase 3 Alpha/ Beta (GSK-3α/β), and stress kinases was downregulated and in protein arrays, Epithelial Cell Adhesion Molecule (EpCAM), Interleukin 6 (IL-6), Granulocyte Macrophage-Colony Stimulating Factor 2 (GM-CSF), Macrophage-Colony Stimulating Factor 1 (M-CSF) and Vascular Endothelial Growth Factor A (VEGF) showed reduced expression in response to MRTX1133. Conclusions: KRAS G12D inhibition reprogrammed the TIME in pancreatic cancer experimental models, reversed tumor growth, increased CD8+ T cell infiltration, decreased myeloid infiltration and elicited sustained tumor regression in response to MRTX1133 combined with immune checkpoint inhibitors. The significant and selective activity of MRTX1133 against the KRAS G13C mutant MDA-MB-231 cell line appears to be linked to the presence of Cyclin Dependent Kinase Inhibitor 2A (CDKN2) deletions as well as of B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) and Tumor Protein P53 (TP53) mutations in contrast to NSCLC cell lines. Therefore, in selected cases of KRAS mutant TNBC, inhibition of KRAS G12D may be used synergistically with immunotherapy
Potential Nanostructures Revealing the Cross-Talk between Nrf2 Signaling Pathway and Neuroinflammation
No full textAlzheimers disease (AD) and Parkinsons disease (PD), the two main causes of dementia, are neurodegenerative diseases in which neuroinflammation is a key factor. α-Synuclein (α-Syn), tau protein, and amyloid-β (Aβ) are among the misfolded proteins that accumulate in these illnesses, leading to mitochondrial dysfunction, oxidative stress and neuroinflammation. In this regard, NF-E2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), plays a crucial role in maintaining redox status, expression of antioxidant genes, and inflammatory response. All of the treatments that have been tried so far to stop protein aggregation have failed in clinical trials. As a result, dementia diagnosis and treatment remain difficult problems. Interestingly, tuning the Nrf2 system can affect the immunometabolic mechanisms and their potential medical applications. Now, it has been the subject of an increasing number of clinical investigations for inflammation and oxidative stress biomarkers and as a novel therapeutic target. However, targeting neuroinflammation by Nrf2 activators also has some limitations like limited pharmacokinetics and pharmacodynamics. Nanotechnology has gained significant interest in various applications, including sensors and therapeutic agents for targeted diseased sites. However, most nanostructures frequently become caught inside innate immune cells rather than reaching the intended target. This review will address these gaps by exploring the role of the Nrf2 pathway in neurodegenerative diseases and examine how custom-designed nanoscale materials can interact with biological systems and how this interaction can impact the nanostructures recognition by cells. Additionally, we will investigate the possible effects of dynamic alterations in the nanomaterials inside biological systems, with a focus on inflammation
YAP1/HIF-1α can Improve Sepsis-Induced ALI by Regulating the Level of Autophagy and Balancing the M1-M2 Polarization of Macrophages
No full textBackground: Acute lung injury (ALI) is an important cause of death in patients with sepsis. The imbalance of M1-M2 polarization of macrophages (MACs) is a momentous factor leading to the progression of sepsis-induced ALI. Moreover, Yes-associated protein 1 (YAP1)/Hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role in regulating inflammatory response, oxidative stress, and autophagy. Therefore, this study aimed to explore whether YAP1/HIF-1α regulates sepsis-induced ALI through autophagy and polarization of macrophages. Methods: Initially, THP-1 cells were cultured in vitro and the phenotype transformation of M1 and M2 was induced by treating them with Lipopolysaccharide (LPS) + Interferon-γ (IFN-γ) or Interleukin-4 (IL-4), respectively. The expression levels of YAP1, HIF-1α, M1 markers, and M2 markers were assessed using Western blot analysis. The impacts of YAP1 and HIF-1α overexpression on M1 markers (inducible Nitric Oxide Synthase (iNOS) and Cluster of Differentiation (CD)80), M2 markers (Arginase-1 (ARG1) and CD206), autophagy markers (Microtubule-associated protein 1A/1B-light chain 3B-II/I (LC3BII/I), Beclin1, and p62), and inflammatory factors (Tumor Necrosis Factor-alpha (TNF-α), IL-6, and IL-10) were evaluated in LPS-induced sepsis ALI cell model in vitro using cell transfection, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analysis. Finally, the expression of LC3B in macrophages was determined using the immunofluorescence method. Results: The expression level of YAP1 was found to be up-regulated in M2 macrophages, while the expression of HIF-1α was up-regulated in M1 macrophages. Furthermore, YAP1 overexpression promoted the transformation of LPS-induced ALI macrophages into M2 phenotype, increased the expression of autophagy factors (LC3BII/I and Beclin1), and reduced the activity of inflammatory factors (TNF-α and IL-6). However, HIF-1α overexpression could balance the M2 polarization of macrophages induced by YAP1 overexpression. Additionally, HIF-1α overexpression elevated the expression of macrophage autophagy factors (p62) and inflammatory factors (TNF-α and IL-6) and reduced the expression of macrophage autophagy factors (LC3BII/I and Beclin1) and the viability of IL-10. Conclusions: In summary, YAP1/HIF-1α can improve sepsis-induced ALI, thereby regulating the level of macrophage autophagy and balancing M1-M2 polarization