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The Lancet. Oncology Jul 2024
Topics: Humans; Trastuzumab; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Receptor, ErbB-2; Camptothecin; Immunoconjugates; Antineoplastic Agents, Immunological; Female; Brain Neoplasms
PubMed: 38936381
DOI: 10.1016/S1470-2045(24)00261-4 -
PloS One 2024To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).
OBJECTIVE
To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).
METHODS
A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway.
RESULTS
ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium.
CONCLUSION
Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway.
Topics: Animals; TOR Serine-Threonine Kinases; Acute Lung Injury; Signal Transduction; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Rats; Male; Glycine; Sulfonamides; Rats, Sprague-Dawley; Lung; Disease Models, Animal
PubMed: 38935660
DOI: 10.1371/journal.pone.0302721 -
PloS One 2024Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream...
Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream signaling pathways that regulate cell growth, proliferation, differentiation, and apoptosis. NTRK-associated mutations often result in oncogenesis and lead to aberrant activation of downstream signaling pathways including MAPK, JAK/STAT, and PLCγ1. This study characterizes the NACC2-NTRK2 oncogenic fusion protein that leads to pilocytic astrocytoma and pediatric glioblastoma. This fusion joins the BTB domain (Broad-complex, Tramtrack, and Bric-a-brac) domain of NACC2 (Nucleus Accumbens-associated protein 2) with the transmembrane helix and tyrosine kinase domain of NTRK2. We focus on identifying critical domains for the biological activity of the fusion protein. Mutations were introduced in the charged pocket of the BTB domain or in the monomer core, based on a structural comparison of the NACC2 BTB domain with that of PLZF, another BTB-containing protein. Mutations were also introduced into the NTRK2-derived portion to allow comparison of two different breakpoints that have been clinically reported. We show that activation of the NTRK2 kinase domain relies on multimerization of the BTB domain in NACC2-NTRK2. Mutations which disrupt BTB-mediated multimerization significantly reduce kinase activity and downstream signaling. The ability of these mutations to abrogate biological activity suggests that BTB domain inhibition could be a potential treatment for NACC2-NTRK2-induced cancers. Removal of the transmembrane helix leads to enhanced stability of the fusion protein and increased activity of the NACC2-NTRK2 fusion, suggesting a mechanism for the oncogenicity of a distinct NACC2-NTRK2 isoform observed in pediatric glioblastoma.
Topics: Humans; Oncogene Proteins, Fusion; Receptor, trkB; Protein Domains; Mutation; Membrane Glycoproteins; Glioblastoma; Signal Transduction; Protein Multimerization
PubMed: 38935636
DOI: 10.1371/journal.pone.0301730 -
PloS One 2024Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor...
Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor receptors, and triggers cell differentiation/survival signaling pathways. To identify signaling molecules involved in the progression of liver diseases, we performed reverse-phase protein microarray (RPMA)-based screening of hepatocytes isolated from humanized mice after acute HCV infection. Acute viral infection in humanized liver mice significantly decreased the level of hepatocyte p-Gab1. Moreover, hepatoma cells upon HCV infection decreased Gab1 mRNA at later times of infection (D3 to D5) and p-Gab1 level was inversely related to the production of TGF-β. In contrast, the level of p-Gab1 was increased in CCL4-induced fibrotic liver. Hepatoma cells showed elevation of p-Gab1, along with an increase in STAT3 and ERK activation, upon treatment with HGF (ligand of HGF receptor/c-Met) and CCL4. In Gab1 knockdown hepatoma cells, cell proliferative signaling activity was reduced but the level of activated caspase-3 was increased. These findings suggest that hepatocyte Gab1 expression may play a role in promoting liver fibrosis progression by triggering ERK activation and inhibiting apoptosis. It implies that the Gab1-mediated signaling pathway would be a promising therapeutic target to treat chronic liver diseases.
Topics: Animals; Hepatocytes; Liver Cirrhosis; Adaptor Proteins, Signal Transducing; Apoptosis; Signal Transduction; Cell Proliferation; Humans; Mice; Proto-Oncogene Proteins c-met; Hepatocyte Growth Factor; Cell Line, Tumor; Hepatitis C
PubMed: 38935609
DOI: 10.1371/journal.pone.0306345 -
Mikrochimica Acta Jun 2024Proteins from different species have been docked with aflatoxin B1 (AFB1) and identified 3 proteins (prostaglandin-E(2)9-reductase from Oryctolagus uniculus,...
Proteins from different species have been docked with aflatoxin B1 (AFB1) and identified 3 proteins (prostaglandin-E(2)9-reductase from Oryctolagus uniculus, proto-oncogene serine/threonine-protein kinase Pim-1 and human immunoglobulin G (hIgG)) as potential candidates to develop an electrochemical sensor. Fluorescence spectroscopy experiments have confirmed the interaction of hIgG with AFB1 with an affinity constant of 4.6 × 10 M. As a proof-of-concept, hIgG was immobilized on carbon nanocomposite (carbon nanotube-nanofiber, CNT-F)-coated glassy carbon electrode (GCE). FT-IR spectra, HR-TEM and BCA assay have confirmed successful immobilization of hIgG on the electrode (hIgG@CNT-F/GCE). The preparation of this protein electrochemical sensor requires only 1 h 36 min, which is fast as compared with preparing an electro immunosensor. hIgG@CNT-F/GCE has displayed an excellent AFB1 limit of detection (0.1 ng/mL), commendable selectivity in the presence of two other mycotoxins (ochratoxin A and patulin) and the detection of AFB1 in spiked peanuts and corn samples.
Topics: Aflatoxin B1; Humans; Electrochemical Techniques; Nanotubes, Carbon; Immunoglobulin G; Limit of Detection; Proto-Oncogene Mas; Electrodes; Biosensing Techniques; Molecular Docking Simulation; Arachis
PubMed: 38935329
DOI: 10.1007/s00604-024-06495-x -
Hematology (Amsterdam, Netherlands) Dec 2024The BCL2 interacting protein 3-like (BNIP3L) protein is involved in multiple myeloma (MM) development and progression. This study aims to explore the connection between...
BACKGROUND
The BCL2 interacting protein 3-like (BNIP3L) protein is involved in multiple myeloma (MM) development and progression. This study aims to explore the connection between BNIP3L single-nucleotide polymorphisms (SNPs) and MM.
METHODS
SNaPshot was used to examine six SNP loci of the BNIP3L gene in enrolled subjects. The relationship between these loci and MM susceptibility and prognosis was explored. Survival analysis was used to evaluate the impact of different factors on patient survival.
RESULTS
The rs2874670 AA genotype and A allele were associated with increased MM risk ( < 0.05). The CCACAC haplotype had a higher frequency in MM, while CCGCAC had a higher frequency in normal patients (all < 0.05). Patients with R-ISS stage I and II had higher survival rates than those with stage III ( < 0.05). Patients, who received chemotherapy followed by autologous stem cell transplantation, had longer survival time than those who only received chemotherapy ( < 0.05). Low levels of LDH and β2-MG were associated with better survival rates ( < 0.05). Cox regression identified that LDH levels, β2-MG levels, and R-ISS staging were the risk factors for the death of MM. Mann-Whitney U test found a significant difference in survival time between MM patients with different BNIP3L rs2874670 genotypes after BD chemotherapy ( < 0.05).
CONCLUSION
To our knowledge, this is the first study to find that BNIP3L rs2874670 could increase MM susceptibility in China. Different BNIP3L rs2874670 genotypes may affect the prognosis of MM patients receiving BD chemotherapy.
Topics: Humans; Multiple Myeloma; Polymorphism, Single Nucleotide; Membrane Proteins; Female; Male; Middle Aged; China; Proto-Oncogene Proteins; Genetic Predisposition to Disease; Adult; Aged; Prognosis; Genotype; Tumor Suppressor Proteins
PubMed: 38934722
DOI: 10.1080/16078454.2024.2367918 -
European Journal of Histochemistry : EJH Jun 2024Cardiomyocyte apoptosis is a complex biological process involving the interaction of many factors and signaling pathways. In hypoxic environment, cardiomyocytes may...
Cardiomyocyte apoptosis is a complex biological process involving the interaction of many factors and signaling pathways. In hypoxic environment, cardiomyocytes may trigger apoptosis due to insufficient energy supply, increased production of oxygen free radicals, and disturbance of intracellular calcium ion balance. The present research aimed to investigate the role of microRNA-29b1 (miR-29b1) in hypoxia-treated cardiomyocytes and its potential mechanism involved. We established an in vitro ischemia model using AC16 and H9C2 cardiomyocytes through hypoxia treatment (1% O2, 48 h). Cell apoptosis was evaluated by flow cytometry using Annexin V FITC-PI staining assay. Moreover, we used Western blot and immunofluorescence analysis to determine the expression of Bcl-2, Bax caspase-3 and Cx43 proteins. We found that miR-29b1 protected AC16 and H9C2 cells from hypoxia-induced injury as evidence that miR-29b1 attenuated the effects of hypoxia treatment on AC16 and H9C2 cell apoptosis after hypoxia treatment. In conclusion, our findings suggest that miR-29b1 may have potential cardiovascular protective effects during ischemia-related myocardial injury.
Topics: Myocytes, Cardiac; Apoptosis; MicroRNAs; Animals; Rats; Cell Hypoxia; Cell Line; Connexin 43; Proto-Oncogene Proteins c-bcl-2
PubMed: 38934067
DOI: 10.4081/ejh.2024.4021 -
Journal of Medical Virology Jun 2024Integration of the human papillomavirus (HPV) genome into the cellular genome is a key event that leads to constitutive expression of viral oncoprotein E6/E7 and drives...
Integration of the human papillomavirus (HPV) genome into the cellular genome is a key event that leads to constitutive expression of viral oncoprotein E6/E7 and drives the progression of cervical cancer. However, HPV integration patterns differ on a case-by-case basis among related malignancies. Next-generation sequencing technologies still face challenges for interrogating HPV integration sites. In this study, utilizing Nanopore long-read sequencing, we identified 452 and 108 potential integration sites from the cervical cancer cell lines (CaSki and HeLa) and five tissue samples, respectively. Based on long Nanopore chimeric reads, we were able to analyze the methylation status of the HPV long control region (LCR), which controls oncogene E6/E7 expression, and to identify transcriptionally-active integrants among the numerous integrants. As a proof of concept, we identified an active HPV integrant in between RUNX2 and CLIC5 on chromosome 6 in the CaSki cell line, which was supported by ATAC-seq, H3K27Ac ChIP-seq, and RNA-seq analysis. Knockout of the active HPV integrant, by the CRISPR/Cas9 system, dramatically crippled cell proliferation and induced cell senescence. In conclusion, identifying transcriptionally-active HPV integrants with Nanopore sequencing can provide viable targets for gene therapy against HPV-associated cancers.
Topics: Humans; Uterine Cervical Neoplasms; Female; Nanopore Sequencing; Virus Integration; Genetic Therapy; Papillomavirus Infections; Cell Line, Tumor; HeLa Cells; Oncogene Proteins, Viral; High-Throughput Nucleotide Sequencing; Papillomaviridae; Human Papillomavirus Viruses
PubMed: 38932482
DOI: 10.1002/jmv.29769 -
Vaccines Jun 2024The objective of this study was to conduct preclinical immunogenicity and efficacy studies with several therapeutic vaccines for human papillomavirus (HPV)-16-associated...
The objective of this study was to conduct preclinical immunogenicity and efficacy studies with several therapeutic vaccines for human papillomavirus (HPV)-16-associated cancers expressing the early antigens E5, E6, and E7 with or without E2. The viral oncoproteins were either expressed by themselves as fusion proteins or the fusion proteins were inserted genetically into herpes simplex virus (HSV)-1 glycoprotein D (gD) which, upon binding to the herpes virus entry mediator (HVEM), inhibits an early T cell checkpoint mediated by the B and T cell mediator (BTLA). This, in turn, lowers the threshold for T cell activation and augments and broadens CD8 T cell responses to the antigens. The fusion antigens were expressed by chimpanzee adenovirus (AdC) vectors. Expression of the HPV antigens within gD was essential for vaccine immunogenicity and efficacy against challenge with TC-1 cells, which express E7 and E6 of HPV-16 but neither E5 nor E2. Unexpectedly, inclusion of E2 increased both CD8 T cell responses to the other oncoproteins of HPV-16 and the effectiveness of the vaccines to cause the regression of sizable TC-1 tumors.
PubMed: 38932345
DOI: 10.3390/vaccines12060616 -
Viruses May 2024Proteins of the Bcl-2 family regulate cellular fate via multiple mechanisms including apoptosis, autophagy, senescence, metabolism, inflammation, redox homeostasis, and... (Review)
Review
Proteins of the Bcl-2 family regulate cellular fate via multiple mechanisms including apoptosis, autophagy, senescence, metabolism, inflammation, redox homeostasis, and calcium flux. There are several regulated cell death (RCD) pathways, including apoptosis and autophagy, that use distinct molecular mechanisms to elicit the death response. However, the same proteins/genes may be deployed in multiple biochemical pathways. In apoptosis, Bcl-2 proteins control the integrity of the mitochondrial outer membrane (MOM) by regulating the formation of pores in the MOM and apoptotic cell death. A number of prosurvival genes populate the genomes of viruses including those of the pro-survival Bcl-2 family. Viral Bcl-2 proteins are sequence and structural homologs of their cellular counterparts and interact with cellular proteins in apoptotic and autophagic pathways, potentially allowing them to modulate these pathways and determine cellular fate.
Topics: Humans; Proto-Oncogene Proteins c-bcl-2; DNA Viruses; Autophagy; Apoptosis; Viral Proteins; Animals; Mitochondrial Membranes
PubMed: 38932171
DOI: 10.3390/v16060879