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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 -
PloS One 2024Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in...
Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in polymeric mucins, a major structural component of mucus, potentially acting as important physiological regulators of mucosal drug absorption, there are no reports that have systematically evaluated the interaction between mucins and drugs. In this study, we assessed the potential interaction between human polymeric mucins (MUC2, MUC5B, and MUC5AC) and various drugs with different chemical profiles by simple centrifugal method and fluorescence analysis. We found that paclitaxel, rifampicin, and theophylline likely induce the aggregation of MUC5B and/or MUC2. In addition, we showed that the binding affinity of drugs for polymeric mucins varied, not only between individual drugs but also among mucin subtypes. Furthermore, we demonstrated that deletion of MUC5AC and MUC5B in A549 cells increased the cytotoxic effects of cyclosporin A and paclitaxel, likely due to loss of mucin-drug interaction. In conclusion, our results indicate the necessity to determine the binding of drugs to mucins and their potential impact on the mucin network property.
Topics: Humans; Paclitaxel; Mucin 5AC; A549 Cells; Drug Interactions; Mucin-5B; Mucins; Mucin-2; Rifampin; Cyclosporine; Protein Binding
PubMed: 38935605
DOI: 10.1371/journal.pone.0306058 -
Critical Care Explorations Jul 2024To identify triggering receptor expressed in myeloid cells-like transcript-1 positive (TLT-1+) microparticles (MPs) and evaluate if their presence is associated with...
High Levels of Triggering Receptor Expressed in Myeloid Cells-Like Transcript-1 Positive, but Not Glycoprotein 1b+, Microparticles Are Associated With Poor Outcomes in Acute Respiratory Distress Syndrome.
OBJECTIVES
To identify triggering receptor expressed in myeloid cells-like transcript-1 positive (TLT-1+) microparticles (MPs) and evaluate if their presence is associated with clinical outcomes and/or disease severity in acute respiratory distress syndrome (ARDS).
DESIGN
Retrospective cohort study.
SETTING
ARDS Network clinical trials.
PATIENTS
A total of 564 patients were diagnosed with ARDS.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Using flow cytometry, we demonstrated the presence of TLT-1+ platelet-derived microparticles (PMP) that bind fibrinogen in plasma samples from fresh donors. We retrospectively quantified TLT-1, glycoprotein (Gp) 1b, or αIIbβIIIa immunopositive microparticles in plasma samples from patients with ARDS enrolled in the ARMA, KARMA, and LARMA (Studies 01 and 03 lower versus higher tidal volume, ketoconazole treatment, and lisofylline treatment Clincial Trials) ARDS Network clinical trials and evaluated the relationship between these measures and clinical outcomes. No associations were found between Gp1b+ MPs and clinical outcomes for any of the cohorts. When stratified by quartile, associations were found for survival, ventilation-free breathing, and thrombocytopenia with αIIbβIIIa+ and TLT-1+ MPs (χ2p < 0.001). Notably, 63 of 64 patients in this study who failed to achieve unassisted breathing had TLT+ PMP in the 75th percentile. In all three cohorts, patients whose TLT+ MP counts were higher than the median had higher Acute Physiology and Chronic Health Evaluation III scores, were more likely to present with thrombocytopenia and were 3.7 times (p < 0.001) more likely to die than patients with lower TLT+ PMP after adjusting for other risk factors.
CONCLUSIONS
Although both αIIbβIIIa+ and TLT+ microparticles (αIIbβIIIa, TLT-1) were associated with mortality, TLT-1+ MPs demonstrated stronger correlations with Acute Physiology and Chronic Health Evaluation III scores, unassisted breathing, and multiple system organ failure. These findings warrant further exploration of the mechanistic role of TLT-1+ PMP in ARDS or acute lung injury progression.
Topics: Humans; Respiratory Distress Syndrome; Male; Female; Retrospective Studies; Middle Aged; Cell-Derived Microparticles; Adult; Membrane Glycoproteins; Aged; Cohort Studies; Platelet Glycoprotein GPIb-IX Complex; Flow Cytometry; Receptors, Immunologic
PubMed: 38935146
DOI: 10.1097/CCE.0000000000001108 -
MBio Jun 2024Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an...
Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an urgent need to develop novel antifungal compounds that are effective against drug-resistant filamentous fungi. Here, we utilized an cell-based high-throughput screen to identify small molecules with antifungal activity that also potentiated triazole activity. The screen identified 16 hits with promising activity against . A nonspirocyclic piperidine, herein named MBX-7591, exhibited synergy with triazole antifungal drugs and activity against pan-azole-resistant isolates. MBX-7591 has additional potent activity against species and CO-dependent activity against . Chemical, genetic, and biochemical mode of action analyses revealed that MBX-7591 increases cell membrane saturation by decreasing oleic acid content. MBX-7591 has low toxicity and shows good efficacy in decreasing fungal burden in a murine model of invasive pulmonary aspergillosis. Taken together, our results suggest MBX-7591 is a promising hit with a novel mode of action for further antifungal drug development to combat the rising incidence of triazole-resistant filamentous fungal infections.IMPORTANCEThe incidence of infections caused by fungi continues to increase with advances in medical therapies. Unfortunately, antifungal drug development has not kept pace with the incidence and importance of fungal infections, with only three major classes of antifungal drugs currently available for use in the clinic. Filamentous fungi, also called molds, are particularly recalcitrant to contemporary antifungal therapies. Here, a recently developed cell reporter strain was utilized to conduct a high-throughput screen to identify small molecules with antifungal activity. An emphasis was placed on small molecules that potentiated the activity of contemporary triazole antifungals and led to the discovery of MBX-7591. MBX-7591 potentiates triazole activity against drug-resistant molds such as and has activity against Mucorales fungi. MBX-7591's mode of action involves inhibiting the conversion of saturated to unsaturated fatty acids, thereby impacting fungal membrane integrity. MBX-7591 is a novel small molecule with antifungal activity poised for lead development.
PubMed: 38934618
DOI: 10.1128/mbio.01166-24 -
Journal of Obstetrics and Gynaecology :... Dec 2024This study aimed to analyse the expression of microRNA-223 (miR-223) in embryo culture medium and its correlation with pregnancy outcomes.
BACKGROUND
This study aimed to analyse the expression of microRNA-223 (miR-223) in embryo culture medium and its correlation with pregnancy outcomes.
METHODS
Two hundred and two patients undergoing in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) were divided into clinical pregnancy group (n = 101) and non-pregnant group (n = 101). The baseline data, clinical indicators, and the expression level of miR-223 in the embryo medium were compared between the two groups. Logistic regression analysis was used to analyse the relationship between each index and the pregnancy outcome. Receiver operator characteristic curve was carried out to evaluate the differential ability of miR-223 in pregnancy status. Bioinformatics methods were used to identify the target genes of miR-223 and elucidate their functions.
RESULTS
Compared with pregnancy group, the non-pregnancy group exhibited a reduction in miR-223 expression ( < 0.001). Multivariate analysis revealed that miR-223 reduction was an independent factor for pregnancy failure ( < 0.05). The ROC curve demonstrated the discriminative capability of miR-223 in distinguishing pregnancy and non-pregnancy. In addition, bioinformatics analysis indicated that the target genes of miR-223 were predominantly located in the endocytic vesicle membrane and were primarily enriched in adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathways.
CONCLUSION
In this study, levels of miR-223 in the embryo culture medium predicted pregnancy outcomes in subjects undergoing IVF/ICSI. Low expression of miR-223 was a risk factor for adverse pregnancy outcomes in subjects.
Topics: Humans; Female; Pregnancy; MicroRNAs; Sperm Injections, Intracytoplasmic; Adult; Fertilization in Vitro; Pregnancy Outcome; Prognosis; ROC Curve; Embryo Culture Techniques
PubMed: 38934480
DOI: 10.1080/01443615.2024.2368773 -
Neural Regeneration Research Jun 2024The N-terminal EF-hand calcium-binding proteins 1-3 (NECAB1-3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one...
The N-terminal EF-hand calcium-binding proteins 1-3 (NECAB1-3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one EF-hand calcium-binding domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members were initially discovered due to their interactions with other proteins. NECAB1 associates with synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NECAB2 interacts with predominantly striatal G-protein-coupled receptors, while NECAB3 partners with amyloid-beta A4 precursor protein-binding family A members 2 and 3, key regulators of β-amyloid production. This demonstrates the capacity of the family for interactions with various classes of proteins. NECAB proteins exhibit distinct subcellular localizations: NECAB1 is found in the nucleus and cytosol, NECAB2 resides in endosomes and the plasma membrane, and NECAB3 is present in the endoplasmic reticulum and Golgi apparatus. The antibiotic biosynthesis monooxygenase domain, an evolutionarily ancient component, is akin to atypical heme oxygenases in prokaryotes but is not well-characterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxygenase domains typically form dimers, suggesting that calcium-mediated conformational changes in NECAB proteins may induce antibiotic biosynthesis monooxygenase domain dimerization, potentially activating some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational changes might influence protein interactions or the subcellular localization of NECAB proteins by controlling the availability of protein-protein interaction domains situated between the EF hands and the antibiotic biosynthesis monooxygenase domain. This review summarizes what is known about genomic organization, tissue expression, intracellular localization, interaction partners, and the physiological and pathophysiological role of the NECAB family.
PubMed: 38934399
DOI: 10.4103/NRR.NRR-D-24-00094 -
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 -
Heliyon Jun 2024Colon cancer is a common gastrointestinal malignancy that ranks third in incidence among gastrointestinal cancers. Therefore, screening bioactive compounds for treatment...
Colon cancer is a common gastrointestinal malignancy that ranks third in incidence among gastrointestinal cancers. Therefore, screening bioactive compounds for treatment of colon cancer is urgently needed. L. (SO) has been demonstrated that the extractions or monomers possess potential anti-tumor effect. In this study, we firstly used cell membrane chromatography (CMC) and ultra-performance liquid chromatography coupled with (quadrupole) time-of-flight mass spectrometry (UHPLC-(Q) TOF-MS/MS) to identify a novel active ingredient, octyl gallate (OG), from SO methanol extract (SO-MtOH). HCT116 and SW620 cells lines were used for research, which showed OG presents great anti-colon cancer effect by inhibiting proliferation, inducing apoptosis, and repressing the migration and invasion. Furthermore, SW620 bearing athymic nude mice was used to investigate the potential antitumor activity , which exhibited OG treatment remarkably lessened the tumor volume. Mechanism studies showed that OG downregulated the PI3K/AKT/mTOR signaling axis and induced apoptosis by upregulating the Bax/Bcl-2 protein and the cleaved caspase-3, caspase-9. In conclusion, our research innovatively applied the method of CMC to intriguingly unearth the potential anti-colon cancer ingredient OG and demonstrated its the great antineoplastic activity, which provide a new insight for researchers efficiently developing the novel apoptosis-inducing compound for colon cancer therapy.
PubMed: 38933948
DOI: 10.1016/j.heliyon.2024.e32230 -
Frontiers in Cell and Developmental... 2024Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and... (Review)
Review
Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and energy provision. Lipid metabolism is necessary for the maintenance of life since it regulates the balance between the processes of synthesis and breakdown. Increasing evidence suggests that cancer cells exhibit abnormal lipid metabolism, significantly affecting their malignant characteristics, including self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. Prominent oncogenic signaling pathways that modulate metabolic gene expression and elevate metabolic enzyme activity include phosphoinositide 3-kinase (PI3K)/AKT, MAPK, NF-kB, Wnt, Notch, and Hippo pathway. Conversely, when metabolic processes are not regulated, they can lead to malfunctions in cellular signal transduction pathways. This, in turn, enables uncontrolled cancer cell growth by providing the necessary energy, building blocks, and redox potentials. Therefore, targeting lipid metabolism-associated oncogenic signaling pathways could be an effective therapeutic approach to decrease cancer incidence and promote survival. This review sheds light on the interactions between lipid reprogramming and signaling pathways in cancer. Exploring lipid metabolism as a target could provide a promising approach for creating anticancer treatments by identifying metabolic inhibitors. Additionally, we have also provided an overview of the drugs targeting lipid metabolism in cancer in this review.
PubMed: 38933330
DOI: 10.3389/fcell.2024.1399065 -
Frontiers in Immunology 2024Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER),... (Review)
Review
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. As a result, conventional hormonal and targeted therapies are largely ineffective, underscoring the urgent need for novel treatment strategies. γδT cells, known for their robust anti-tumor properties, show considerable potential in TNBC treatment as they can identify and eliminate tumor cells without reliance on MHC restrictions. These cells demonstrate extensive proliferation both and , and can directly target tumors through cytotoxic effects or indirectly by promoting other immune responses. Studies suggest that expansion and adoptive transfer strategies targeting Vδ2 and Vδ1 γδT cell subtypes have shown promise in preclinical TNBC models. This review compiles and discusses the existing literature on the primary subgroups of γδT cells, their roles in cancer therapy, their contributions to tumor cell cytotoxicity and immune modulation, and proposes potential strategies for future γδT cell-based immunotherapies in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Animals; Female; Receptors, Antigen, T-Cell, gamma-delta; Intraepithelial Lymphocytes; Immunotherapy, Adoptive; Immunotherapy
PubMed: 38933280
DOI: 10.3389/fimmu.2024.1420107