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Investigating the Role of FASLG in Inducing T Cell Exhaustion to Facilitate Immune Escape in Non-Small Cell Lung Cancer: A Bioinformatics-Based Study
No full textBackground: Non-small cell lung cancer (NSCLC) represents the predominant pathological subtype of lung cancer in China. Amidst the advent of precision medicine, immunotherapy has emerged as a pivotal approach in managing malignant neoplasms, substantially improving patient prognosis and survival rates. However, the efficacy of immunotherapy remains limited, primarily attributed to the development of resistance among advanced-stage patients. This study used bioinformatics methodologies to analyze and identify potential key genes governing immune resistance in NSCLC, offering novel insights into therapeutic avenues. Methods: Gene expression datasets (GSE126044 and GSE135222) encompassing NSCLC cases with immunotherapy resistance and control groups were retrieved from the Gene Expression Omnibus (GEO) repository. Differential gene expression analysis was conducted using Gene Expression Omnibus 2 R (GEO2R) with criteria set at |log FC (fold change)| ≥1 and p < 0.05. Subsequent analyses involved Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Ontology (GO) functional annotation, Protein-Protein Interaction (PPI) network construction, and Gene Set Enrichment Analysis (GSEA). The findings were visualized through volcano plots and box plots in the R program. Candidate genes were cross-validated with Genecard database entries and scrutinized against existing literature for clinical relevance. The association between key genes, immune cells, and immune-associated gene expressions was analyzed using the Tumor Immune Estimation Resource (TIMER) database. Immunohistochemistry assays were employed to assess the differentially expressed genes (DEGs) in lung cancer tissues. Results: Sixty-four upregulated DEGs were obtained from datasets GSE126044 and GSE135222. PPI network analysis identified one cluster and twelve candidate genes, further corroborated through module examination of common DEGs. Integration with Genecard database entries and literature confirmed Fas Ligand (FASLG) as a pivotal gene. KEGG and GSEA pathway analyses unveiled potential mechanisms predominantly related to the interaction between immune cell functions and cytokines, especially T cells. Analysis in the TIMER database revealed a significant positive correlation between FASLG expression and six types of infiltrating immune cells, as well as specific immune cell subsets, alongside three immune checkpoint-associated molecules: Cluster of Differentiation 274 (CD274), Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4), and Programmed Cell Death Protein 1 (PDCD1) (p-value < 0.05). Furthermore, in The Cancer Genome Atlas (TCGA) database, FASLG was strongly associated with T cell gene markers and regulatory factors associated with T cell exhaustion, demonstrating statistical significance (p-value < 0.05). Immunohistochemical results preliminarily confirmed the significant upregulation of FASLG in lung cancer tissues. Conclusion: The identification of key genes and associated signaling cascades deepens our understanding of the molecular mechanisms governing immunotherapy resistance in NSCLC. Notably, FASLG is a potential facilitator of immune escape in NSCLC tumor cells by promoting T cell exhaustion, highlighting NSCLC as a viable target for anticancer interventions
In Situ Drug Delivery Investigation through Characterization and Application of Carbon-Based Nanomaterials: A Promising Approach for Treating Viral Diseases
No full textBackground: This study focuses on a medication targeting the primary protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), aiming to inhibit in vitro viral replication across diverse experiments. At the onset of the coronavirus disease of 2019 (COVID-19) pandemic, only general therapy was available; however, an emergency application license has recently been granted for an oral antiviral in the U.S. Nirmatrelvir, an antiviral drug developed by Pfizer, operates as an orally effective 3 Cysteine-like protease inhibitor. Methods: This work evaluates the inhibitory potential of nirmatrelvir against the coronavirus when delivered using carbon nanomaterials. The direct electron transfer principle, elucidated through the quantum mechanics method of density functional theory (DFT), guides the drug delivery process. The evaluation involves the Becke, 3-parameter, Lee–Yang–Parr (B3LYP)/6-311+G (d,p) theoretical method to assess the affinity of carbon nanomaterials for nirmatrelvir using nuclear quadrupole resonance, nuclear magnetic resonance, thermodynamic specifications, and frontier molecular orbital theory. Results: Theoretical calculations demonstrated that carbon nanotubes effectively capture nirmatrelvir, as indicated by nuclear quadrupole resonance, nuclear magnetic resonance, thermodynamic specifications, and frontier molecular orbital theory using the B3LYP/6-311+G (d,p) method. This study suggests that combining carbon nanotube (CNT) and nirmatrelvir may offer a viable formula for drug delivery, supported by quantum mechanics computations and physicochemical properties of nuclear quadrupole resonance (NQR), nuclear magnetic resonance (NMR), infrared (IR), and ultraviolet/visible (UV-VIS) approaches. Conclusions: In this work, network pharmacology, metabolite analysis, and molecular simulation were employed to elucidate the biochemical basis of the health-promoting effects of nirmatrelvir in drug delivery with CNT. This research article explores the efficacy of the drug, metabolites, and potential interactions of some medicinal plants with coronavirus-induced pathogenesis
Notoginsenoside R1 Decreases Cell Apoptosis in the Brains of Rats with Cerebral Infarction by Activating Notch1 Signaling Pathway
No full textBackground: Cerebral infarction (CI) often leads to disability or cognitive deficits with limited effective therapeutic options. This study investigated the effect and mechanism of Notoginsenoside R1 (NGR1) on protecting cells from apoptosis in rat CI models. Methods: Sprague Dawley (SD) rats were used to establish CI models through middle cerebral artery occlusion (MCAO) treatment. Hematoxylin-eosin (H&E) staining was used to observe pathological changes. Cell apoptosis was assessed by Bcl-2 apoptosis regulator (Bcl-2)/Bcl-2 associated X (Bax), cleaved caspase-3, and cleaved caspase-9 levels determined by western blot and enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) was used to evaluate levels of hes family bHLH transcription factor 1 (Hes1) and Notch receptor 1 (Notch1). Additionally, Notch1 pathway activation was regulated by the Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and Notch 1 activator valproic acid (VPA), and the consequent effect on brain cell apoptosis was determined. Results: In CI rat brains, the levels of cleaved caspase-3 and cleaved caspase-9 were elevated (p < 0.001), while Bcl-2/Bax was decreased (p < 0.001). NGR1 reversed these changes (p < 0.01). Hes1 and Notch1 levels were reduced in CI rat brains (p < 0.001) and were reversed by NGR1 (p < 0.001). Furthermore, compared to NGR1-treated CI rats, additional DAPT/VPA decreased/increased levels of Hes1, Notch1, Bcl-2/Bax (p < 0.001), and increased/decreased cleaved caspase-3 and cleaved caspase-9 levels (p < 0.001). Conclusion: NGR1 can decrease cell apoptosis in the brains of CI rats by activating the Notch1 signaling, presenting a novel therapeutic strategy with potential therapeutic targets for treating CI
LRPPRC Promotes Colorectal Cancer Cell Invasion and Metastasis through Tumor Cell Epithelial-Mesenchymal Transition
No full textBackground: The leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) functions to regulate cell cytoskeleton. This study assessed LRPPRC expression in colorectal cancer (CRC) for association with the clinicopathological features from patients and then investigated the impact of LRPPRC expression on CRC cells in vitro and in vivo. Material and Methods: Tissue microarrays were built using 75 cases of each really normal and CRC tissues or 75-paired normal and CRC tissues for immunohistochemical analysis of LRPPRC expression. CRC cell lines were grown and assessed for tumor cell migration and invasion using wound healing and transwell assays. Changes in mRNA and protein expression in CRC cells were assayed using western blot and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), respectively. Knockdown or overexpression of LRPPRC was conducted using siRNA and cDNA transfections, respectively. Next, a nude mouse xenograft assay was performed to verify the impact of LRPPRC expressions in vivo. Results: LRPPRC was overexpressed in CRC vs. real normal and paired normal tissues (p < 0.05), which was associated with CRC lymph node and distant metastases, and advanced clinical stages. In vitro, knockdown of LRPPRC expression inhibited CRC LOVO cell migration and invasion, whereas LRPPRC overexpression promoted CRC HCT116 cell migration and invasion. Moreover, LRPPRC overexpression upregulated Vimentin, N-cadherin, and Snail, and downregulated E-cadherin protein, whereas knockdown of LRPPRC expression had opposite results, suggesting increase in CRC cell epithelial-mesenchymal transition (EMT). In addition, knockdown of LRPPRC expression suppressed growth of colorectal cancer cell xenografts in mice. Conclusions: LRPPRC could be an oncogene or had an oncogenic activity in CRC
Ginkgolide B Ameliorates White Matter Injury after Ischemic Stroke through Regulating Biological Signature of Neuroglial Cells
No full textBackground: Ischemic stroke (IS) continues to be the foremost cause of mortality and disability worldwide. Ginkgolide B (GB), an originally natural terpene lactone, is widely employed in the treatment of cerebrovascular disease. Nevertheless, a comprehensive understanding of the precise role and underlying mechanisms of GB in white matter injury after IS necessitates further elucidation. The objective of the present study was to assess the impact of GB on white matter injury and to analyze alterations in the types and gene expression of neuroglial cells using single-cell RNA sequencing (scRNA-seq). Methods: Ninety-four male C57BL/6 mice were categorized into four groups: (1) Sham control (n = 21); (2) middle cerebral artery occlusion (MCAO) mice receiving PBS vehicle (MCAO+PBS) group (n = 29); (3) MCAO mice subjected to a 1-week-long GB treatment (MCAO+GB1w) group (n = 13); (4) MCAO mice undergoing a 2-week-long GB treatment (MCAO+GB2w) group (n = 31). GB or PBS was administered to the mice following ischemic cerebral injury induced by middle cerebral artery occlusion (MCAO). Neurobehavioral state was assessed using foot fault (FF) and rotarod (RR) tests. White matter injury and microglial cell subtypes were determined through immunofluorescence. ScRNA-seq was employed to illustrate the crucial biological processes and gene expressions influenced by GB in white matter injury after MCAO. Results: Our findings indicated a significant prolongation in the latency to fall during RR test and a decrease in the FF rate for both forelimb and hindlimb in the MCAO+GB2w group compared to the MCAO+PBS group. The demyelinating damage to white matter in the MCAO+GB2w group was notably milder than that in the MCAO+PBS group (p < 0.05), as evidenced by a significantly increased MBP/SMI-32 ratio. Immunofluorescence analysis revealed an elevated proportion of M2 microglial cells and a decreased level of M1 microglial cells in the MCAO+GB2w group compared to the MCAO+PBS group on the 14th day, 21st day, and 28th day (p < 0.05). ScRNA-seq findings demonstrated that GB provides protection against ischemia/reperfusion (I/R)-induced white matter injury by upregulating critical processes such as myelin sheath reproduction and oligodendrocyte maturation. Gene Ontology (GO) enrichment and analysis of differentially expressed genes (DEGs) revealed a significant upregulation of proteolipid protein 1 (PLP1), alphaB-Crystallin (CRYAB), ß-tubulin 4A (TUBB4A), constitutive androstane receptor 2 (CAR2), and ATPase Na+/K+ transporting subunit beta 2 (ATP1B2) in the myelin sheath pathway of microglial cells. Similarly, echinoderm microtubule-associated protein-like 1 (EML1), Heat shock proteins 72 (HSPA1A), signal peptide peptidase-like 2b (SPPL2B), and alpha 1A (TUBA1A) were significantly upregulated in oligodendrocytes (p < 0.05). Cell trajectory analysis indicated that oligodendrocytes underwent induction towards more mature subclusters following GB administration. Conclusions: GB has the potential to alleviate white matter injury and neurobehavioral dysfunction following MCAO by increasing the proportion of M2 microglial cells, decreasing M1 microglial cells, and promoting oligodendrocyte maturation to enhance myelination
Causal Association of Total Bilirubin and Albumin Levels with Lung Cancer Risk: A Mendelian Randomization Study
No full textBackground: Our study aimed to examine the causal relationship between total bilirubin and albumin levels and the risk of developing lung cancer (LC). Previous studies have suggested that the antioxidant properties of these two biomarkers may potentially inhibit cancer development. However, the available evidence on the relationship between total bilirubin and albumin levels and the risk of LC remains inconsistent. Method: We conducted a two-sample Mendelian randomization (TSMR) study to investigate the association between total bilirubin and albumin levels and the risk of developing LC and assess their causality. We retrieved aggregate statistical datasets from publicly accessible genome-wide association studies (GWAS) of bilirubin and albumin and utilized them as the exposure. Results: Our findings indicated that bilirubin and albumin levels were associated with an increased risk of LC. The findings were as follows: bilirubin: odds ratio (OR) = 1.341%, 95% confidence interval (CI): 1.076–1.672, p = 0.009; albumin: OR = 1.582%, 95% CI: 1.077–2.323, p = 0.019. Conclusion: This TSMR analysis indicates that bilirubin and albumin levels positively correlate with an increased risk of LC. These findings contribute to a deeper comprehension of the causes of LC and offer insights into its prevention
Integrated Gut Microbiome–Metabolome Profiles of Diarrhea-Predominant Irritable Bowel Syndrome: A Study from a Chinese Cohort
Get PDFBackground: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder, yet its underlying mechanism remains incompletely understood. This study aimed to elucidate gut microbiome dysbiosis and metabolic perturbations among Chinese patients with diarrhea-predominant IBS (IBS-D). Methods: Fecal samples were collected from 55 IBS-D patients (according to Rome IV criteria) and 29 healthy controls. Gut microbiome-metabolome signatures were obtained through 16S ribonucleic acid (rRNA) amplicon sequencing and untargeted metabolomics. Integrated bioinformatics analysis was conducted to investigate microbiome-metabolome characteristics in IBS-D patients. Results: Significant differences in microbiome profiles were observed between IBS-D patients and healthy volunteers. Utilizing machine learning algorithms, our investigation revealed a notable increase in gut microbes, including Sutterella, Lachnospira, Bacteroides, and Fusobacterium, in the IBS-D patients (p < 0.05). Conversely, Bifidobacterium, Blautia, and Romboutsia exhibited a decrease in IBS-D patients (p < 0.05). Furthermore, functional analysis indicated potential alterations in gut lipopolysaccharide (LPS) biosynthesis and disruptions in energy metabolism functions among IBS-D patients. In terms of metabolome profiles, significant upregulation was observed in metabolites such as 5′-S-methyl-5′-thioadenosine, S-adenosyl-methionine, creatine, adenine, and gamma-aminobutyric acid (GABA) in individuals with IBS-D (p < 0.05), suggesting a potentially pivotal role of these metabolites in the microbiota-gut-brain axis. Additionally, our study identified several significant associations between metabolites and microbes, further enhancing our understanding of the intricate interplay within the IBS-D microbiome. Conclusions: Our research highlights a microbiome-metabolome pattern in individuals with IBS-D, indicating that gut microbiome and fecal metabolites can serve as valuable indicators to distinguish between IBS-D patients and healthy individuals
N-Acetylcysteine Inhibits NLRP3 Inflammasome Activation by Suppressing the Noncanonical Pyroptosis Pathway, Thereby Promoting Uterine Quiescence
No full textBackground: The NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the immune microenvironment. Therefore, we investigated the involvement of NLRP3 in the inflammatory response associated with term and preterm birth, as well as the potential of N-acetylcysteine (NAC) to mitigate this inflammatory response. Methods: First, we induced infectious preterm birth in mice using Lipopolysaccharide (LPS) and treated them with NAC. Next, LPS was used to trigger inflammation in uterine smooth muscle cells (USMC), which were then treated with NAC. The levels of cleaved caspase-4/5/11, NLRP3, and Apoptosis-associated speck-like protein containing CARD (ASC) proteins in both the myometrium and USMC were determined by western blot. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the levels of caspase-1, interleukin-1β (IL-1β), and IL-18 in the myometrium and USMC. Subsequently, siRNA targeting NLRP3 was transfected into LPS-treated USMC, and the expression levels of NLRP3, oxytocin receptor (OTR), ASC, connexin 43 (CX43), and inflammatory cytokines were evaluated using western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: The NLRP3 inflammasome, cleaved caspase-4/5/11, and ASC were found to be upregulated in USMC and myometrium tissues treated with LPS (p < 0.01). Administration of NAC not only prolonged the duration of pregnancy but also suppressed the activation of NLRP3 and the noncanonical pyroptosis pathway (p < 0.01 and p < 0.001). Deletion of NLRP3 under LPS conditions led to a decrease in the expressions of OTR and CX43 (p < 0.05), along with a reduction in the levels of associated inflammatory factors (p < 0.05). Conclusions: NAC inhibits immune inflammation and promotes uterine quiescence by suppressing the noncanonical pyroptosis pathway and NLRP3 inflammasome activation
Cytokine Profile in Nasal-Type Extranodal Nature Killer/T-Cell Lymphoma-Associated Hemophagocytic Syndrome
No full textBackground: The role of cytokines in predicting the diagnosis of extranodal nature killer/T-cell lymphoma-associated hemophagocytic syndrome (ENKL-LAHS) has been reported. This retrospective study aimed to analyze the cytokine profile in nasal type ENKL-LAHS. Methods: Sixty patients diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) were divided into two groups: ENKL-LAHS group (n = 30) and ENKL group (n = 30), based on the presence of lymphoma-associated hemophagocytic syndrome (LAHS). Peripheral blood cytokine levels were compared between the two groups. A logistic regression model was applied to assess the relationship between serum cytokine levels and ENKL-LAHS. The predictive values of serum cytokines for ENKL-LAHS were determined through receiver operating characteristic (ROC) curves. Results: Compared to the ENKL group, the ENKL-LAHS group exhibited significantly elevated levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.001), granulocyte-colony stimulating factor (G-CSF) (p = 0.001), interferon-gamma (IFN-γ) (p = 0.003), interleukin (IL)-10 (p < 0.001), IL-15 (p < 0.001), IL-1 receptor antagonist (IL-1ra) (p < 0.001), IL-8 (p < 0.001), macrophage inflammatory protein 1α (MIP-1α) (p < 0.001), interferon-gamma inducible protein-10 (IP-10) (p < 0.001), MIP-1β (p < 0.001) and tumor necrosis factor α (TNF-α) (p < 0.001). Conversely, the levels of monocyte chemoattractant protein-1 (MCP-1) (p = 0.002) and soluble CD40 ligand (sCD40L) (p < 0.001) were significantly decreased. Logistic multivariate analysis revealed that the concentrations of cytokines IL-8 (p < 0.001), IL-10 (p = 0.016), IL-15 (p = 0.026), IFN-γ (p = 0.034), GM-CSF (p = 0.012), G-CSF (p = 0.001), sCD40L (p < 0.001), and TNF-α (p = 0.024) correlated with ENKL-LAHS. ROC curve analysis showed that the sCD40L/GM-CSF/IL-8 model exhibited better predictive value (the area under the curve (AUC): 0.973). Conclusion: sCD40L, GM-CSF, and IL-8 have a strong predictive value for ENKL-LAHS and can serve as reliable predictors for this condition
Effect of Colchicine on Systemic Inflammation, Peripheral Blood CD4+ T Cell Subsets and Oxidative Stress in Patients with Coronary Heart Disease Combined with Gout after Percutaneous Coronary Intervention
No full textBackground & Objective: Colchicine improves cardiovascular outcomes in patients with coronary heart disease, but the underlying mechanisms remain incompletely elucidated. The aim of this study was to evaluate the effects of colchicine on systemic inflammation, peripheral blood CD4+ T cell subsets, and oxidative stress after percutaneous coronary intervention in patients with coronary heart disease combined with gout from the perspective of population study. Methods: From January 2019 to June 2022, a total of 128 patients with coronary heart disease combined with gout who underwent percutaneous coronary intervention (PCI) at our hospital were retrospectively collected and divided into colchicine group (n = 64) and control group (n = 64) according to whether colchicine was routinely used or not. Systemic inflammation (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and hypersensitivity C-reactive protein (hs-CRP)), peripheral blood CD4+ T cell subsets (Th1 cells, Th17 cells, and regulatory T cells), and oxidative stress indicators (serum superoxide dismutase (SOD) and malondialdehyde (MDA)) were compared between the two groups after PCI. hs-CRP ≥2 mg/L was defined as a patient at risk of residual inflammatory. Logistic regression was used to analyze the association between colchicine treatment and the risk of residual inflammation. Results: There was no significant difference between the two groups in terms of age, gender, smoking history, disease history, body mass index (BMI), time from symptom onset to PCI, blood pressure, hypersensitivity troponin I (hs-TnI), neutrophils, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), serum creatinine, and the equilibrium was comparable (p > 0.05). After PCI treatment, TNF-α and IL-6 levels were significantly decreased in both groups, and the levels of TNF-α and IL-6 in the colchicine group were significantly lower than control group (TNF-α: 22.5 ± 4.9 vs 41.6 ± 4.1 μg/L; IL-6: 21.3 ± 12.8 vs 40.9 ± 17.5 ng/L; both p < 0.001). Patients in the colchicine group had a significantly proportion of risk of residual inflammation compared with controls (37.5% vs 62.5%, p = 0.005). Logistic regression showed that, using the control group as a reference, we still found that colchicine use was independently associated with a reduced risk of residual inflammation when corrected for other confounders (odds ratio [OR], 0.372; 95% confidence interval [CI], 0.156–0.889; p = 0.026). Regarding peripheral blood CD4+ T cell subsets, Th1 cell, Th17 cell, and regulatory T cell counts were significantly higher in the colchicine group than control group after PCI treatment (p < 0.01). As for oxidative stress indicators, SOD levels were significantly higher and MDA levels were significantly lower in the colchicine group after PCI treatment compared with the control group (p < 0.001). Conclusions: Colchicine administration was associated with reduced systemic inflammatory indexed, promoted proliferation of peripheral blood CD4+ T cells, and improved oxidative stress levels in patients with coronary heart disease combined with gout after PCI