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Biomedicine & Pharmacotherapy =... Apr 2024Sphingolipid transporter 1 (SPNS1) is a significant differentially expressed gene (DEGs) in esophageal squamous cell carcinoma (ESCC). According to 3 pairs clinic...
Sphingolipid transporter 1 (SPNS1) is a significant differentially expressed gene (DEGs) in esophageal squamous cell carcinoma (ESCC). According to 3 pairs clinic cohorts, transcriptomic (155 pairs of ESCC samples and GSE53624, and proteomic data from PXD021701 including 124 ESCC samples) we found that SPNS1 was significantly higher in ESCC tissues compared to adjacent normal esophagus tissues. ESCC patients with high SPNS1 had a significantly poorer clinical prognosis than those with low SPNS1. Knockdown of SPNS1 significantly inhibited the proliferation, migration, and invasion abilities of ESCC cells, while promoting apoptosis. And overexpression of SPNS1 exhibited opposite functions. Furthermore, ESCC cells became more sensitive to 5-fluorouracil (5-FU) when SPNS1 was knocked down. Transcriptome sequencing revealed that NEU1 was one significant DEG affected by SPNS1 and positively correlated with SPNS1 expression. Oseltamivir phosphate (OP), one NEU1 inhibitor, markedly reversed 5-FU resistance, migration, and proliferation induced by high expression of SPNS1 both in vivo and in vitro. Our findings indicated that SPNS1 might promote the progression of ESCC by upregulating NEU1 expression and influencing chemotherapy sensitivity. These results provide new perceptions into potential therapeutic targets for ESCC treatment. The present study aimed to investigate the role and underlying mechanism of SPNS1 in ESCC.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Oseltamivir; Esophageal Neoplasms; Proteomics; Cell Line, Tumor; Cell Proliferation; Fluorouracil; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 38460365
DOI: 10.1016/j.biopha.2024.116367 -
Viruses Jan 2022Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid...
Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.
Topics: A549 Cells; Animals; Antiviral Agents; Chemokines; Cytokines; Dibenzothiepins; Drug Therapy, Combination; Female; Humans; Influenza A Virus, H5N1 Subtype; Influenza A virus; Lung; Mice; Mice, Inbred BALB C; Morpholines; Orthomyxoviridae Infections; Oseltamivir; Pneumonia; Pyridones; Sequence Analysis; Triazines; Virus Replication
PubMed: 35062315
DOI: 10.3390/v14010111 -
Tetrahedron Sep 2020Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use... (Review)
Review
Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. (-)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been developed to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago in the quest for a truly efficient, safe, cost-effective and environmentally benign synthetic procedure. We have selected a few representative routes to give a clear account of the past, present and the future with the advent of enabling technologies.
PubMed: 32839628
DOI: 10.1016/j.tet.2020.131440 -
Minerva Medica Jul 2023
PubMed: 37486204
DOI: 10.23736/S0026-4806.23.08816-X -
Cells Mar 2024Understanding the role of biased G protein-coupled receptor (GPCR) agonism in receptor signaling may provide novel insights into the opposing effects mediated by...
Functional Selectivity of Cannabinoid Type 1 G Protein-Coupled Receptor Agonists in Transactivating Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition Metastatic Phenotype.
Understanding the role of biased G protein-coupled receptor (GPCR) agonism in receptor signaling may provide novel insights into the opposing effects mediated by cannabinoids, particularly in cancer and cancer metastasis. GPCRs can have more than one active state, a phenomenon called either 'biased agonism', 'functional selectivity', or 'ligand-directed signaling'. However, there are increasing arrays of cannabinoid allosteric ligands with different degrees of modulation, called 'biased modulation', that can vary dramatically in a probe- and pathway-specific manner, not from simple differences in orthosteric ligand efficacy or stimulus-response coupling. Here, emerging evidence proposes the involvement of CB1 GPCRs in a novel biased GPCR signaling paradigm involving the crosstalk between neuraminidase-1 (Neu-1) and matrix metalloproteinase-9 (MMP-9) in the activation of glycosylated receptors through the modification of the receptor glycosylation state. The study findings highlighted the role of CB1 agonists AM-404, Aravnil, and Olvanil in significantly inducing Neu-1 sialidase activity in a dose-dependent fashion in RAW-Blue, PANC-1, and SW-620 cells. This approach was further substantiated by findings that the neuromedin B receptor inhibitor, BIM-23127, MMP-9 inhibitor, MMP9i, and Neu-1 inhibitor, oseltamivir phosphate, could specifically block CB1 agonist-induced Neu-1 sialidase activity. Additionally, we found that CB1 receptors exist in a multimeric receptor complex with Neu-1 in naïve, unstimulated RAW-Blue, PANC-1, and SW-620 cells. This complex implies a molecular link that regulates the interaction and signaling mechanism among these molecules present on the cell surface. Moreover, the study results demonstrate that CB1 agonists induce NFκB-dependent secretory alkaline phosphatase (SEAP) activity in influencing the expression of epithelial-mesenchymal markers, E-cadherin, and vimentin in SW-620 cells, albeit the impact on E-cadherin expression is less pronounced compared to vimentin. In essence, this innovative research begins to elucidate an entirely new molecular mechanism involving a GPCR signaling paradigm in which cannabinoids, as epigenetic stimuli, may traverse to influence gene expression and contribute to cancer and cancer metastasis.
Topics: Cannabinoid Receptor Agonists; Matrix Metalloproteinase 9; Vimentin; Ligands; Glycosylation; Neuraminidase; Receptors, G-Protein-Coupled; Cannabinoids; Epithelial-Mesenchymal Transition; Cadherins; Neoplasms
PubMed: 38534324
DOI: 10.3390/cells13060480 -
Nutrients Jun 2024Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing...
Artificial and Natural Sweeteners Biased T1R2/T1R3 Taste Receptors Transactivate Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition of Metastatic Phenotype.
Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.
Topics: Humans; Epithelial-Mesenchymal Transition; Receptors, G-Protein-Coupled; Sweetening Agents; Cell Line, Tumor; Matrix Metalloproteinase 9; Neoplasm Metastasis; Glycosylation; Signal Transduction; Phenotype; Animals; Taste; Cell Movement; Neuraminidase
PubMed: 38931195
DOI: 10.3390/nu16121840 -
Frontiers in Medicine 2023The occurrence of a co-infection involving four distinct respiratory pathogens could be underestimated. Here, we report the case of a 72-year-old woman who presented to...
The occurrence of a co-infection involving four distinct respiratory pathogens could be underestimated. Here, we report the case of a 72-year-old woman who presented to a community hospital with a cough productive of sputum as her main clinical manifestation. Antibody detection of common respiratory pathogens revealed potential co-infection with influenza A, influenza B, respiratory syncytial virus, and . We treated her with 75 mg oseltamivir phosphate administered orally twice daily for 5 days, 0.5 g azithromycin administered orally for 5 days, and 0.3 g acetylcysteine aerosol inhaled twice daily for 3 days. The patient showed a favorable outcome on the eighth day after early diagnosis and treatment. Since co-infection with these four pathogens is rare, we performed an extensive PubMed search of similar cases and carried out a systematic review to analyze the epidemiology, clinical manifestations, transmission route, susceptible population, and outcomes of these four different pathogens. Our report highlights the importance for general practitioners to be vigilant about the possibility of mixed infections when a patient presents with respiratory symptoms. Although these symptoms may be mild, early diagnosis and timely treatment could improve outcomes. Additionally, further research is warranted to explore the potential influence of SARS-CoV-2 infection on the co-occurrence of multiple respiratory pathogens.
PubMed: 38259842
DOI: 10.3389/fmed.2023.1325482