PD-1/PD-L1 axis induced host immunosuppression via PI3K/Akt/mTOR signalling pathway in piglets infected by Glaesserella Parasuis
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC10998357 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Infection of piglets with Glaesserella parasuis (G. parasuis) induces host immunosuppression. However, the mechanism underlying the immunosuppression of piglets remains unclear. Activation of the PD-1/PD-L1 axis has been shown to trigger host immunosuppression. Baicalin possesses anti-inflammatory and immunomodulatory functions. However, whether baicalin inhibits PD-1/PD-L1 activation and thus alleviates host immunosuppression has not been investigated. In this study, the effect of baicalin on the attenuation of piglet immunosuppression induced by G. parasuis was evaluated. Seventy piglets were randomly divided into the control group, infection group, levamisole group, BMS-1 group, 25 mg/kg baicalin group, 50 mg/kg baicalin group and 100 mg/kg baicalin group. Following pretreatment with levamisole, BMS-1 or baicalin, the piglets were challenged with 1 × 108 CFU of G. parasuis. Our results showed that baicalin, levamisole and BMS-1 modified routine blood indicators and biochemical parameters; downregulated IL-1β, IL-10, IL-18, TNF-α and IFN-γ mRNA expression; and upregulated IL-2 and IL-8 mRNA expression in blood. Baicalin, levamisole and BMS-1 increased the proportions of CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+ T cells and CD3-CD21+ B cells in the splenocyte population, increased the proportions of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells in the blood, and inhibited PD-1/PD-L1 and TIM-3 activation. Baicalin, levamisole and BMS-1 reduced p-PI3K, p-Akt, and p-mTOR expression, the p-MEK1/2/MEK1/2 and p-ERK1/2/ERK1/2 ratios and increased RAS expression. Baicalin, levamisole and BMS-1 provided substantial protection against G. parasuis challenge and relieved tissue histopathological damage. Our findings might provide new strategies for controlling G. parasuis infection and other immunosuppressive diseases.
| S-EPMC11285455 | biostudies-literature
Project description:In this study, we compared the virulence of the most common serovars of Glaesserella parasuis in China, serovars 4, 5, 12, and 13 (36 strains in total) in BALB/c mice and piglets. In mice, the median lethal doses (LD50s) of the four serovars were roughly 9.80 × 107-4.60 × 109 CFU, 2.10 × 108-8.85 × 109 CFU, 4.81 × 107-7.01 × 109 CFU, and 1.75 × 108-8.45 × 108 CFU, respectively. Serovar 13 showed the strongest virulence, followed by serovar 4, serovar 12, and serovar 5, but a significant difference in virulence was only observed between serovars 5 and 13. The virulence of strains of the same serovars differed significantly in piglets. Virulent and attenuated strains were present in all serovars, but serovar 5 was the most virulent in piglets, followed by serovars 13, 4, and 12. A significant difference in virulence was observed between serovars 5 and 4 and between serovars 5 and 12. However, the virulence of serovars 5 and 13 did not differ significantly. This comprehensive analysis of G. parasuis virulence in mice and piglets demonstrated that: (1) the order of virulence of the four domestic epidemic serovars (from strongest to weakest) in piglets was serovars 5, 13, 4, and 12; (2) both virulent and attenuated strains were present in all serovars, so virulence did not necessarily correlate with serovar; (3) Although G. parasuis was fatal in BALB/c mice, its virulence is inconsistent with that in piglets, indicating that BALB/c mice are inadequate as an alternative model of G. parasuis infection.
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Project description:The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer. MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice. The mechanistic studies investigated cellular affinity of a new 1,2,4-triazine derivative by measuring levels of intracellular/extracellular signal molecules participating in tumorigenesis. The results revealed that MM-129 significantly reduced tumor growth in mice challenged with DLD-1 and HT-29 cells. It exerted the ability to inhibit intracellular molecules promoting tumorigenesis and inducing cell cycle arrest, like Akt, mTOR, and CDK2. Simultaneously, it was able to downregulate PD-L1 expression, which involves immunological self-tolerance. Combined administration of MM-129 and 5-fluorouracil (5-FU) additionally amplified these effects, which were manifest as an increase population of cells in the G0/G1 phase. A novel 1,2,4-triazine derivative with a dual mechanism of antitumor activity-MM-129, may act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemotherapy of colon cancer.
| S-EPMC8268553 | biostudies-literature
Project description:Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.
| S-EPMC5550428 | biostudies-literature
Project description:The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.
| S-EPMC7110906 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (OSCC) is a lethal digestive tract malignancy with limited effective interventions. This study aims to explore a new potential inhibitor on OSCC and investigate the underlying mechanisms. Based on a drug screen of an FDA-proven library consisting of 1404 compounds, we demonstrated that Omipalisib, a dual PI3K/mTOR inhibitor, markedly inhibited cell proliferation and colony formation in a panel of OSCC cell lines. Mechanistically, Omipalisib induced G0/G1 phase cell cycle arrest and apoptosis. Moreover, RNA-seq, KEGG and GSEA confirmed that the PI3K/mTOR signalling pathway is the primary target of Omipalisib in OSCC cells. Omipalisib treatment suppressed the PI3K/mTOR signalling pathway. Furthermore, Omipalisib exerted a significant antineoplastic effect on OSCC tumour xenografts in BALB/c nude mice without obvious side effects. The present study supports the rationale for using Omipalisib as a therapeutic approach for OSCC cases and suggests the potential clinical evaluation of this strategy.
2020-01-11 | GSE143462 | GEO
Project description:Anti-programmed cell death 1 (PD-1) or anti-PD-ligand (L) 1 drugs, as classic immune checkpoint inhibitors, are considered promising treatment strategies for tumors. In clinical practice, some cancer patients experience drug resistance and disease progression in the process of anti-PD-1/PD-L1 immunotherapy. Tumor-associated macrophages (TAMs) play key roles in regulating PD-1/PD-L1 immunosuppression by inhibiting the recruitment and function of T cells through cytokines, superficial immune checkpoint ligands, and exosomes. There are several therapies available to recover the anticancer efficacy of PD-1/PD-L1 inhibitors by targeting TAMs, including the inhibition of TAM differentiation and re-education of TAM activation. In this review, we will summarize the roles and mechanisms of TAMs in PD-1/PD-L1 blocker resistance. Furthermore, we will discuss the therapies that were designed to deplete TAMs, re-educate TAMs, and intervene with chemokines secreted by TAMs and exosomes from M1 macrophages, providing more potential options to improve the efficacy of PD-1/PD-L1 inhibitors.
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Project description: Not available
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Project description:Glaesserella (formerly Haemophilus) parasuis causes Glässer's disease, which results in high economic loss in the swine industry. To understand the polymicrobial interactions of G. parasuis and the nasal microbiota, the statistical association patterns of nasal colonizing bacteria with virulent and non-virulent strains of G. parasuis were studied accounting for the farm management practices as potential risk factors for the occurrence of Glässer's disease. The nasal microbiota from 51 weaned-piglets from four farms with Glässer's disease and three farms with no respiratory diseases was previously characterized and included in this study. The presence of virulent and/or non-virulent G. parasuis strains in the nasal cavities was determined in order to establish the potential association with other members of the nasal microbiota. Multivariate logistic and linear regression models were performed among the various members of nasal microbiota and G. parasuis. The multi-site production system and disease presence in the farm were both significantly associated with the presence of G. parasuis virulent strains in the nose of the piglets. Differential bacterial associations were observed with virulent or non-virulent G. parasuis. Chitinophagaceae, Corynebacteriaceae and Corynebacterium were positively associated with the virulent G. parasuis strains, while Enterobacteriaceae, Peptostreptococcaceae, Clostridium XI, and Escherichia/Shigella were negatively associated with virulent G. parasuis. On the other hand, Flavobacteriaceae, Planobacterium, and Phascolarctobacterium were positively associated with the non-virulent G. parasuis strains, while Rikenellaceae, Enterococcaceae, Odoribacter, and Corynebacterium were negatively associated with non-virulent G. parasuis. In conclusion, the nasal microbiota communities showed variations in the association with the G. parasuis strains type.
| S-EPMC6996185 | biostudies-literature
Project description:Chemoresistance is a common and thorny problem in the treatment of osteosarcoma (OS), which obstructs the response of relapse or metastasis of OS to chemotherapy and leads to the unfavorable prognosis of OS patients. Cyclin L1 (CCNL1) is a non-canonical cyclin that plays an important role in the regulation of tumor cell proliferation and lymph node metastasis. In this work, we explored the impact of CCNL1 expression levels on proliferation, migration, and Adriamycin (ADM) resistance in OS and related mechanisms. We found that CCNL1 expression levels were significantly associated with clinical prognosis of patients with OS and CCNL1 could promote OS proliferation and migration. In addition, we also revealed that cellular CCNL1 was significantly increased in ADM-resistant OS cells and promoted ADM resistance. The PI3K/AKT-mTOR pathway is involved in CCNL1-mediated ADM resistance in OS. In summary, CCNL1 is involved in the progression of ADM resistance and OS through the PI3K/AKT-mTOR pathway, which will provide a new clue to the mechanism of ADM resistance and a potential target for the treatment of ADM-resistant OS.
| S-EPMC11315378 | biostudies-literature