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Drug Discovery Today Jun 2024Lenvatinib is a multikinase inhibitor that suppresses vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived... (Review)
Review
Lenvatinib is a multikinase inhibitor that suppresses vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor α (PDGFRα), as well as the proto-oncogenes RET and KIT. Lenvatinib has been approved by the US Food and Drug Administration (FDA) for the first-line treatment of hepatocellular carcinoma (HCC) due to its superior efficacy when compared to sorafenib. Unfortunately, the development of drug resistance to lenvatinib is becoming increasingly common. Thus, there is an urgent need to identify the factors that lead to drug resistance and ways to mitigate it. We summarize the molecular mechanisms that lead to lenvatinib resistance (LR) in HCC, which involve programmed cell death (PCD), translocation processes, and changes in the tumor microenvironment (TME), and provide strategies to reverse resistance.
PubMed: 38936692
DOI: 10.1016/j.drudis.2024.104069 -
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 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 -
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 -
Nutrients Jun 2024Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental...
Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.
Topics: Fatty Acids, Monounsaturated; Glycation End Products, Advanced; Female; Animals; Pregnancy; Receptor for Advanced Glycation End Products; Rats; Muscle, Skeletal; Reactive Oxygen Species; Cell Line; Cell Survival; Mice; Dietary Supplements; Proto-Oncogene Proteins c-akt; Oxidative Stress; Insulin Resistance; Humans; Phosphorylation; Rats, Sprague-Dawley; Pregnancy in Diabetics; Male; Fetal Development
PubMed: 38931253
DOI: 10.3390/nu16121898 -
Nutrients Jun 2024, a polyphenol-rich plant, holds potential for improving inflammation, but its mechanisms are not well understood. Therefore, this study employed network pharmacology...
, a polyphenol-rich plant, holds potential for improving inflammation, but its mechanisms are not well understood. Therefore, this study employed network pharmacology and molecular docking to explore the mechanism by which ameliorates inflammation. In this study, 29 kinds of active ingredients were obtained via data mining. Five main active components were screened out for improving inflammation, which were flemichin D, naringenin, chrysophanol, genistein and orobol. In total, 52 core targets were identified, including AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor (TNF), B-cell lymphoma-2 (BCL2), serum albumin (ALB), and estrogen receptor 1 (ESR1). Gene ontology (GO) enrichment analysis identified 2331 entries related to biological processes, 98 entries associated with cellular components, and 203 entries linked to molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis yielded 149 pathways, including those involved in EGFR tyrosine kinase inhibitor resistance, endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking results showed strong binding effects between the main active components and the core targets, with binding energies less than -5 kcal/mol. In summary, this study preliminarily elucidated the underlying mechanisms by which , through a multi-component, multi-target, and multi-pathway approach, ameliorates inflammation. This provides a theoretical foundation for the subsequent application of in inflammation amelioration.
Topics: Molecular Docking Simulation; Network Pharmacology; Inflammation; Humans; Signal Transduction; Fabaceae; Anti-Inflammatory Agents; Proto-Oncogene Proteins c-akt; Plant Extracts
PubMed: 38931205
DOI: 10.3390/nu16121850 -
Nutrients Jun 2024Nucleotides (NTs) act as pivotal regulatory factors in numerous biological processes, playing indispensable roles in growth, development, and metabolism across...
Nucleotides (NTs) act as pivotal regulatory factors in numerous biological processes, playing indispensable roles in growth, development, and metabolism across organisms. This study delves into the effects of exogenous NTs on hepatic insulin resistance using palmitic-acid-induced HepG2 cells, administering interventions at three distinct dosage levels of exogenous NTs. The findings underscore that exogenous NT intervention augments glucose consumption in HepG2 cells, modulates the expression of glycogen-synthesis-related enzymes (glycogen synthase kinase 3β and glycogen synthase), and influences glycogen content. Additionally, it governs the expression levels of hepatic enzymes (hexokinase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase). Moreover, exogenous NT intervention orchestrates insulin signaling pathway (insulin receptor substrate-1, protein kinase B, and forkhead box protein O1) and AMP-activated protein kinase (AMPK) activity in HepG2 cells. Furthermore, exogenous NT intervention fine-tunes the expression levels of oxidative stress-related markers (malondialdehyde, glutathione peroxidase, and NADPH oxidase 4) and the expression of inflammation-related nuclear transcription factor (NF-κB). Lastly, exogenous NT intervention regulates the expression levels of glucose transporter proteins (GLUTs). Consequently, exogenous NTs ameliorate insulin resistance in HepG2 cells by modulating the IRS-1/AKT/FOXO1 pathways and regulate glucose consumption, glycogen content, insulin signaling pathways, AMPK activity, oxidative stress, and inflammatory status.
Topics: Humans; Hep G2 Cells; Insulin Resistance; Palmitic Acid; Insulin Receptor Substrate Proteins; Forkhead Box Protein O1; Proto-Oncogene Proteins c-akt; Signal Transduction; Nucleotides; Glucose; Oxidative Stress; Glycogen; Insulin
PubMed: 38931156
DOI: 10.3390/nu16121801