2,968 results on '"death receptors"'
Search Results
2. Endoplasmic reticulum stress and death receptor-mediated apoptosis in the neuronal differentiation of adult adipose-derived stromal cells
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Zhang, Pingshu, Li, Wen, Zheng, Xinyue, Luo, Hongjie, Liu, Qing, Long, Qingxi, Yan, Qi, and Yuan, Xiaodong
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- 2024
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3. Lidocaine could promote the cuproptosis through up-regulating the long noncoding RNA DNMBP-AS1 in Hep-2 cells.
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Liu, Wei, Yu, Yi, He, Yi, and Lv, Meihong
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LINCRNA , *LOCAL anesthetics , *DEATH receptors , *GENE expression , *LIDOCAINE - Abstract
Background: Lidocaine is a traditional local anesthetic, which has been reported to trigger apoptosis through the mitochondrial pathway, independent of death receptor signaling. Cuproptosis is a copper triggered mitochondrial cell death mode. In this study, we explored the biological effects of lidocaine on cuproptosis in Hep-2 cells and studied the relevant mechanisms. Methods: quantitative RT-PCR was used to measure the expression level of long noncoding RNA (IncRNA) DNMBP-AS1. DNMBP-AS1 siRNA (si-DNMBP-AS1) were transfected into Hep-2 cells to verify the roles of DNMBP-AS1 in cuproptosis. 24 h treatment with 20 nM elesclomol and 2 µM CuCl2 was performed to promote the occurrence of Cuproptosis. Cell proliferation, migration and apoptosis assays ware utilized to analyze biological effect of lidocaine and DNMBP-AS1 on Hep-2 cells. Active caspase-3 were also determined after treatment. Results: DNMBP-AS1 was significantly upregulated during cuproptosis in Hep-2 cells. The si-DNMBP-AS1 significantly increased the cell viability with nonactivated caspase-3, promoted the cell migration and suppress the cuproptosis. Lidocaine was cytotoxic to the Hep-2 cells in a dose- and time-dependent manner. Exposure to 10 µM of lidocaine for 24 h did not reduce the viability or activated the caspase-3, but significantly increased the expression of DNMBP-AS1, and promote the cuproptosis. Anymore, si-DNMBP-AS1 reversed the pro-cuproptosis function of lidocaine. Conclusions: lidocaine was cytotoxic to Hep-2 cells in a time- and dose-dependent manner, promoted the cuproptosis through up-regulating DNMBP-AS1. The results of this study offered initial optimism that lidocaine could be used in an adjuvant or neoadjuvant fashion in cancer treatment. [ABSTRACT FROM AUTHOR] more...
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- 2025
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4. The anti-melanoma roles and mechanisms of tricholoma isoflavone derivative CA028.
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Liang, Cheng, Jiang, Jianfu, Li, Jinkai, Lin, Xiao, Huang, Wenjun, Lai, Keng Po, and Chen, Jian
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DEATH receptors ,MEDICAL sciences ,SKIN cancer ,GENE ontology ,MELANOMA - Abstract
As a form of skin cancer, melanoma's incidence rate is continuing to rise globally. Therefore, there is an urgent need to find new agents to improve survival in melanoma patients. Isoflavones, a class of phytoestrogens, are primarily found in soy and other legumes. Cumulating evidence demonstrates that isoflavones exhibits significant anti-tumor properties and is beneficial for the prevention and treatment of melanoma. In the present study, we aim to investigate the anti-melanoma role of tricholoma isoflavone derivative CA028. By using in vitro melanoma cell line models, A375 and A2058 and in vivo xenograft mouse model, our results indicate that melanoma proliferation, migration, and invasion are attenuated following CA028 treatment. In addition, the treatment of CA028 induced cell apoptosis of melanoma. Finally, we addressed the mechanism of CA028 against melanoma by comparative transcriptomic analysis. The results of gene ontology highlighted the involvement of CA028's targets in the cell proliferation, cell apoptosis, and migration ability of melanoma cells. Furthermore, Ingenuity Pathway Analysis constructed the network involved in the apoptotic roles of CA028 through targeting p53 signaling and death receptor signaling. For the first time, our data suggested the possible use of modified isoflavone for therapeutic applications against melanoma. [ABSTRACT FROM AUTHOR] more...
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- 2025
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5. An antibiotic that mediates immune destruction of senescent cancer cells.
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Raffi, Gabriele Casagrande, Jian Chen, Xuezhao Feng, Zhen Chen, Lieftink, Cor, Shuang Deng, Jinzhe Mo, Chuting Zeng, Steur, Marit, Jing Wang, Bleijerveld, Onno B., Hoekman, Liesbeth, van der Wel, Nicole, Feng Wang, Beijersbergen, Roderick, Jian Zheng, Bernards, Rene, and Liqin Wang more...
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INTRACELLULAR calcium , *DEATH receptors , *CELL death , *CANCER cells , *REACTIVE oxygen species - Abstract
Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18). [ABSTRACT FROM AUTHOR] more...
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- 2024
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6. Unveiling the Mechanisms of Apoptosis Induction by Deep‐Sea‐Derived Polyketide‐Terpenoid Hybrids from Penicillium allii‐sativi: A Focus on Mitochondrial and mTOR Pathways.
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Xie, Chun‐Lan, Wu, Tai‐Zong, Zhang, Duo, Wang, Yuan, Lin, Ting, Chen, Hai‐Feng, Zhang, Xiao‐Kun, and Yang, Xian‐Wen
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CELL cycle , *DEATH receptors , *SALICYLIC acid , *HELA cells , *CELL death - Abstract
Comprehensive Summary: A chemical investigation of the deep‐sea‐derived fungus Penicillium allii‐sativi MCCC 3A00580 resulted in the discovery of four new meroterpenoids (1—4) and one related known co‐metabolite (5). These meroterpenoids showcase unique carbon skeletons featuring a common drimane sesquiterpene part with highly diverse polyketide units. Particularly, compound 1 incorporates a salicylic acid moiety while 2 possesses a rare peroxide bridge in the polyketide part. The structures of new compounds were assigned by extensive spectroscopic analysis, quantum calculations, and biogenetic considerations. Notably, 3 significantly blocked the mTOR signaling pathway, resulting in the arrest of cell cycle at G0‐G1 phase and triggering mitochondrial apoptosis in Hela cells. While the previously reported co‐metabolite macrophorin A (MPA) effectively triggered cell death in MDA‐MB‐231 cancer cells by activating apoptosis pathways involving death receptors, mitochondria, mTOR, and TNF. [ABSTRACT FROM AUTHOR] more...
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- 2024
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7. V‐domain immunoglobulin suppressor of T‐cell activation and programmed death receptor 1 dual checkpoint blockade enhances antitumour immunity and survival in glioblastoma.
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Jin, Shasha, Li, Tao, Liu, Liu, Gao, Ting, Zhang, Tingting, Yuan, Dingyi, Di, Jianwen, Guo, Zhanying, Luo, Zhijie, Yuan, Haoliang, and Liu, Jun
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BRAIN tumors , *IMMUNE checkpoint proteins , *DEATH receptors , *GLIOBLASTOMA multiforme , *OVERALL survival - Abstract
Background and Purpose Experimental Approach Key Results The current therapy cannot meet the needs of glioblastoma (GBM). V‐domain immunoglobulin suppressor of T‐cell activation (VISTA) is significantly up‐regulated in GBM patients; however, its therapeutic potential in GBM is still unclear.Flow cytometry was used to detect the expression of VISTA and the co‐expression pattern of VISTA and programmed death receptor 1 (PD‐1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of
α ‐VISTA monotherapy andα ‐VISTA combined withα ‐PD‐1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data.Compared with normal mice, the frequency of VISTA expression and co‐expression of VISTA and PD‐1 on tumour‐infiltrating lymphocytes (TILs) in tumour‐bearing mice was increased. Anti‐VISTA monotherapy significantly up‐regulated multiple immune stimulation‐related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD‐1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8+ T cells played an important role in this process. In addition, we found that the expression of VISTA and PD‐1 was significantly up‐regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD‐1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD‐1 may achieve clinical transformation in GBM. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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8. PD-1 / PD-L1 抑制剂治疗非小细胞肺癌并发免疫 相关不良反应预测模型的构建与验证.
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谢红妹, 周 俭, 陈惠东, and 苏 坤
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PROGRAMMED death-ligand 1 , *DRUG side effects , *RECEIVER operating characteristic curves , *NON-small-cell lung carcinoma , *DEATH receptors , *HEMOPHILIACS - Abstract
OBJECTIVE: To analyze the influencing factors of immune-related adverse drug reactions in the treatment of non-small cell lung cancer (NSCLC) with programmed death receptor 1 (PD-1) / programmed death receptor ligand 1 (PD-L1) inhibitors, and to construct the predictive model. METHODS: A total of 280 patients with NSCLC admitted into the hospital from Jan. 2021 to Oct. 2023 were retrospectively analyzed, which were randomly divided into the modeling set (196 cases) and validation set (84 cases) according to a ratio of 7 ∶ 3, and the patients in the modeling group were divided into complicating group and non-complicating group according to whether there were complicated with immune-related adverse drug reactions during treatment. Multivariate Logistic regression was used to analyze the influencing factors of immune-related adverse drug reactions in NSCLC patients, and R software was used to construct the prediction model. Bootstrap method was adopted to conduct internal validation on the model, the receiver operating characteristic curve (ROC), calibration curve and decision curve (DCA) were drawn to evaluate the predictive efficacy, calibration degree and clinical net benefit of the model respectively. RESULTS: The incidence of immune-related adverse drug reactions in NSCLC patients treated with inhibitors was 32. 50% (91 / 280); the proportion of patients age ≥65 years old, with smoking history and low expression of PD-L1, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), neutrophil / lymphocyte ratio (NLR) and platelet / lymphocyte ratio (PLR) of the complicating group were higher than those of the non-complicating group, with statistically significant differences (P < 0. 05). Results of further Logistic regression analysis showed that age ≥65 years old, smoking history, low expression of PD-L1, elevated IL-6, TNF-α, NLR and PLR were risk factors for immune-related adverse drug reactions in NSCLC patients (P < 0. 05); the areas under the predictive curve of the modeling set and the validation set were 0. 863 and 0. 851, respectively; the P values of Hosmer-Lemeshow test results of both the modeling set and the validation set were > 0. 05, with good degree of fitting; results of DCA showed that the nomogram models of both the modeling set and the validation set had good clinical net benefits. CONCLUSIONS: This study has identified the influencing factors of immune-related adverse drug reactions in NSCLC patients treated with PD-1/ PD-L1 inhibitors, and the predictive model constructed accordingly is helpful for clinical identification of high-risk patients, so as to intervene in advance to reduce adverse drug reactions. [ABSTRACT FROM AUTHOR] more...
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- 2024
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9. A randomized controlled study of neoadjuvant metformin with chemotherapy in nondiabetic breast cancer women: The METNEO study.
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Serageldin, Manar A., El‐Bassiouny, Noha A., El‐Kerm, Yasser, Aly, Rania G., Helmy, Maged W., El‐Mas, Mahmoud M., and Kassem, Amira B.
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CANCER stem cells , *BREAST cancer , *NEOADJUVANT chemotherapy , *DEATH receptors , *GENE expression , *METFORMIN , *BREAST , *PACLITAXEL - Abstract
Aims: Clinical data demonstrate that metformin exhibits antiproliferative, proapoptotic and antimetastatic actions. Here, correlative molecular studies were undertaken to determine the roles of transmembrane tumour necrosis factor‐related apoptosis‐inducing ligand death receptors (DRs) and CD133, a glycoprotein biomarker of breast cancer (BC) stem cells, in the advantageous action of metformin on pathological and clinical outcomes in BC patients on neoadjuvant chemotherapy. Methods: We randomly assigned 70 nondiabetic BC patients in a 1:1 ratio to either neoadjuvant AC‐T chemotherapy (4 cycles of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2, followed by 12 cycles of weekly paclitaxel 80 mg/m2) or AC‐T with adjunct metformin (850 mg twice/day). The expressions of DR4, DR5 and CD133 were quantified in excised tissue samples with residual tumour cells. Results: The overall clinical response (odds ratio: 22.67 [2.77–185.18], P =.004), breast‐conserving surgery (odds ratio: 3.67 [1.303–10.321], P =.014) and pathological complete response (β = 2.49 ± 1.13 [0.274–4.712], P =.028) rates were significantly improved in the metformin arm. Tissues obtained from the metformin arm had upregulated mRNA expression of DR4 (Mean delta cycle thresholds ± standard error of the mean: 2.68 ± 0.25 vs. 4.87 ± 0.53, P =.0003) and DR5 (0.21 ± 0.25 vs. 4.29 ± 0.95, P =.0004) compared to control arm. The enhanced DR expression negatively correlated with that of CD133 + BC stem cells, which was significantly reduced by metformin at both cytoplasmic/membranous (43.48 vs. 100.00%, P <.0001) and nuclear sites (4.35 vs. 95.00%, P <.0001). Conclusion: Metformin improves clinical and pathological responses to neoadjuvant AC‐T chemotherapy in BC via prompting directionally opposite changes in DRs (increments) and CD133 + (decrements) expressions. This study was registered in ClinicalTrials.gov (registration number: NCT04170465, https://clinicaltrials.gov/ct2/show/NCT04170465). [ABSTRACT FROM AUTHOR] more...
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- 2024
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10. Immune checkpoints are suppressed during pregnancy following influenza A virus infection.
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Vanders, Rebecca L., Gomez, Henry M., Daly, Katie, Wark, Peter A., Horvat, Jay C., and Hansbro, Philip M.
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IMMUNE checkpoint proteins , *PREGNANCY outcomes , *CELL receptors , *IMMUNE checkpoint inhibitors , *DEATH receptors - Abstract
Influenza A virus (IAV) infection is a major health risk during pregnancy. Although vaccination and antiviral agents are widely used and reduce IAV-induced symptoms, they are not sufficient to control IAV infections in pregnancy, especially during pandemics. Respiratory viruses like IAV exploit immune alterations that occur during pregnancy, including the upregulation of immune checkpoint proteins (ICPs) like programmed death ligand-1 (PDL1), programmed cell death receptor 1 (PD1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). We hypothesize that blocking expression of PDL1 on innate immune cells will improve maternal immunity following IAV infection. We used murine models of IAV infection during pregnancy with and without treatment with the immune checkpoint inhibitor (ICI), a-PDL1. Pregnant and nonpregnant mice were infected with mouse-adapted IAV (A/PR/8) and assessed at 3 days post infection (3 dpi). Lung cells were analyzed using flow cytometry. Lung mRNA expression of inflammatory and antiviral markers and histology was measured. Protein concentrations of inflammatory and antiviral markers, as well as viral titers were measured from lung bronchiolar lavage fluid (BALF). Lung function was also assessed. Following IAV infection, immune cells from pregnant mice had significant increases in the ICPs, PDL1, PD1, and CTLA4. a-PDL1 treatment effectively suppressed these ICPs and increased the activation marker, CD86. a-PDL1 treatment also reduced lung inflammatory cell infiltration and viral titers, increased antiviral responses, and improved lung function. Overall, IAV infection in pregnancy activates key inhibitory ICPs, leading to worsened disease outcomes. a-PDL1 treatment during IAV infection in pregnancy is an effective method to reduce ICP expression and improve overall immune cell responses. NEW & NOTEWORTHY: Influenza infection worsens disease outcomes during pregnancy; however, treatment with anti-PDL1 can restore immune function during pregnancy. [ABSTRACT FROM AUTHOR] more...
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- 2024
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11. Fisetin reduces the resistance of MOLT-4 and K562 cells to TRAIL-induced apoptosis through upregulation of TRAIL receptors.
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Liu, Lei, Hussain, Shaik Althaf, and Hu, Xiaoyan
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TRAIL protein ,CANCER cells ,HISTONE deacetylase inhibitors ,DEATH receptors ,REGULATOR genes - Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that is capable of apoptosis induction selectively in tumor cells. Although TRAIL has been harnessed in numerous clinical trials, resistance to TRAIL-induced apoptosis is a major challenge ahead of this therapy in various cancer models as well as in leukemia. Since histone deacetylases (HDACs) are known to affect drug resistance in malignant cells, the present study aimed to evaluate the potential of fisetin for sensitization of MOLT-4 and K-562 leukemic cells to TRAIL-induced apoptosis. The MOLT-4 and K-562 cells were treated with increasing concentrations of fisetin and its impact on the growth inhibition and apoptosis induction of TRAIL were evaluated by MTT and Annexin V/7-AAD assays. The impact of fisetin on the mRNA and protein expression levels of apoptosis regulatory genes such as BIRC2/c-IAP1, CFLAR/cFLIP, CASP3, CASP7, CASPP9, TNFRSF10A/DR4, TNFRSF10B/DR5, and BID were examined by PCR array, qRT-PCR, and flow cytometry. Pre-treatment of MOLT-4 and K-562 cells with fisetin reduced the IC50 of TRAIL in growth inhibition along with an improvement in apoptosis induction by TRAIL. The expression of the BIRC2 gene encoding antiapoptotic protein c-IAP1 downregulated in the fisetin-treated cells while the expressions of TNFRSF10A and TNFRSF10B encoding TRAIL death receptors increased. Fisetin demonstrated a potential for alleviating the TRAIL resistance by modulating the apoptosis regulatory factors and improving the expressions of TRAIL receptors that could facilitate the application of TRAIL in cancer therapies. [ABSTRACT FROM AUTHOR] more...
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- 2024
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12. Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway.
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Zhang, Na, Liu, Jianping, Guo, Rui, Yan, Lingjie, Yang, Yuanxin, Shi, Chen, Zhang, Mengmeng, Shan, Bing, Li, Wanjin, Gu, Jinyang, and Xu, Daichao
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TUMOR necrosis factors , *CYTOTOXINS , *CELL death , *PALMITOYLATION , *PROTEIN kinases , *DEATH receptors - Abstract
Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S -palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases. [Display omitted] • RIPK1 is S -palmitoylated in TNFR1 signaling complex upon TNF stimulation • Palmitoylation licenses the kinase activity and cytotoxicity of RIPK1 in TNF pathway • DHHC5 catalyzes RIPK1 palmitoylation, depending on RIPK1 K63-linked ubiquitination • DHHC5 is amplified by fatty acid and promotes RIPK1-dependent liver damage in MASH Zhang et al. demonstrate that TNF induces RIPK1 palmitoylation, which is mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, to license RIPK1 kinase activity and cytotoxicity when cell death checkpoints are blocked. DHHC5 is amplified by fatty acid, contributing to increased RIPK1 cytotoxicity observed in metabolic dysfunction-associated steatohepatitis. [ABSTRACT FROM AUTHOR] more...
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- 2024
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13. Insights into the historical trajectory and research trends of immune checkpoint blockade in colorectal cancer: visualization and bibliometric analysis.
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Chang, Yonglong, Zhou, Xuhui, Nie, Kechao, Liu, Jinhui, and Zhang, Sifang
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BIBLIOMETRICS ,DRUG side effects ,IMMUNE checkpoint proteins ,DEATH receptors ,UNIVERSAL healthcare - Abstract
Background: Colorectal cancer (CRC) is a malignant tumor that poses a significant threat to human health due to rising incidence and mortality rates. In recent years, immune checkpoint blockade (ICB) therapy, represented by Programmed death receptor 1 (PD-1), T-lymphocyte-associated protein 4 (CTLA-4), and others, has been widely applied in CRC and has achieved encouraging results in some patients and has become a hot topic in both clinical and basic research. Objective: This study undertakes a comprehensive bibliometric analysis of ICB research in CRC, aiming to evaluate the current status, identify future trends, and provide scientific insights for researchers and decision-makers. Methods: Utilizing the Web of Science Core Collection (WoSCC), articles focusing on ICB in CRC from 2000 to 2022 were retrieved. Knowledge mapping and bibliometric analysis were conducted using tools such as CiteSpace, VOSviewer, SCImago Graphicay, and the R package bibliometrix. Results: 6,718 publications were analyzed from 24,846 institutions across 639 regions. Temporally, ICB research in CRC is rapidly advancing, led by the USA and China with extensive global collaborations. Sun Yat-sen University from China stands out as the institution with the highest number of publications. Professor Thierry Andre from Sorbonne University in France is identified as a prolific author in this field, engaging in extensive collaboration for clinical trials on a global scale. Publications related to this research topic were published in 1,142 academic journals, demonstrating a positive co-citation relationship. Key clustering and burst terms analysis indicate that current research on ICB in CRC has shifted from basic experiments to clinical trials and from universal healthcare to precision medicine. Conclusion: ICB therapies have shown substantial progress in CRC, highlighting their therapeutic potential. Research trends emphasize deeper drug mechanisms, treatment efficacy prediction, managing immune-related adverse events, and exploring novel drug delivery methods. Collaboration across borders remains crucial for further advancements. [ABSTRACT FROM AUTHOR] more...
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- 2024
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14. Bladder Cancer Treatments in the Age of Personalized Medicine: A Comprehensive Review of Potential Radiosensitivity Biomarkers.
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Feghaly, Charbel, Challita, Rafka, Hadir, Hanine Bou, Mobayed, Tala, Bitar, Tarek Al, Harbi, Mohammad, Ghorayeb, Hala, El-Hassan, Rana, and Bodgi, Larry
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DOUBLE-strand DNA breaks , *BLADDER cancer , *DEATH receptors , *DNA repair , *CANCER patients - Abstract
Bladder cancer is one of the most frequently diagnosed cancers in men. While cystectomy remains the primary treatment, advances in radiotherapy and chemotherapy have highlighted the value of bladder-preserving strategies, which can also enhance patients' quality of life. Despise these advances, around 20% of patients may still require salvage cystectomy due to tumor radioresistance. This underscores the need to develop radiosensitivity predictive assays. Radiotherapy acts by inducing DNA damage, primarily through DNA double-strand breaks, which can significantly affect treatment outcomes if left unrepaired. In addition to activating DNA repair pathways, the response to radiation also involves the tumor microenvironment, cell death pathways, immune responses and different types of cell death and proliferation receptors. In recent years, personalized medicine, which tailors treatments to individual patients, has gained increasing attention in cancer care. The development of chemo- and radiosensitivity predictive assays has become a key focus of cancer research. Despite the potential impact of such assays on bladder cancer treatment, there is still no reliable test that can help clinicians and informs patients in choosing the best treatment. This review aims to highlight studies that attempted to characterize bladder cancer radiosensitivity and to discuss the potential biomarkers that could be used to develop bladder cancer radiosensitivity predictive assays. [ABSTRACT FROM AUTHOR] more...
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- 2024
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15. Clinical characteristics and prognosis of liver injury induced by immune checkpoint inhibitors in patients with malignancies: A real‐world retrospective study.
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Jiang, Ying, Lv, Minzhi, Jin, Zhiping, Wu, Yi, Li, Xiaoyu, and Zhang, Ningping
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IMMUNE checkpoint inhibitors , *INJURY risk factors , *HEPATITIS B virus , *CELL receptors , *DEATH receptors - Abstract
Aims: Programmed cell death receptor (ligand)‐1 inhibitors (PD‐(L)1), as the preferred immunotherapy, have been widely used in the Chinese mainland and drug‐induced liver injury (DILI) has been reported. The study aimed to investigate the clinical features or risk factors for immunotherapy‐related DILI. Methods: Patients who received PD‐(L)1 inhibitors from January 2020 to July 2021 were retrospectively reviewed. The likelihood of DILI was adjudicated by the Roussel‐Uclaf causality assessment. Results: A total of 1175 patients were included in the study and 89 patients (7.6%) developed DILI, of which 12 (13.5%) progressed to acute liver failure (ALF) and three (3.4%) died. Among the DILI population, 56 (62.9%) had a cholestatic pattern and exhibited a prolonged treatment course and duration for resolution compared to the hepatocellular and mixed patterns. Hepatocellular carcinoma (HCC), hepatitis B virus (HBV) and abnormal baseline of alkaline phosphatase (ALP) had increased risks of DILI by 2.1‐fold (95% confidence interval [CI], 1.231–3.621), 1.9‐fold [95% CI, 1.123–3.325] and 2.1‐fold [95% CI, 1.317–3.508], respectively. The model for end‐stage liver disease (MELD) score had a c‐statistic of 0.894 (95% CI, 0.778–1.000) with a sensitivity of 67% and a specificity of 95% for poor outcomes. COX analysis showed that the MELD ≥ 18 was predictive of immunotherapy‐related ALF or death. Conclusions: PD‐(L)1 inhibitor‐related liver injury manifests primarily as a cholestatic pattern, on which corticosteroid treatment has minimal effect compared to hepatocellular and mixed patterns. MELD score ≥ 18 at the time of liver injury performed best in the prediction of ALF or death in immune checkpoint inhibitor (ICI)‐related DILI. [ABSTRACT FROM AUTHOR] more...
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- 2024
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16. Amelanotic Melanoma—Biochemical and Molecular Induction Pathways.
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Misiąg, Piotr, Molik, Klaudia, Kisielewska, Monika, Typek, Paulina, Skowron, Izabela, Karwowska, Anna, Kuźnicki, Jacek, Wojno, Aleksandra, Ekiert, Marcin, and Choromańska, Anna
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FECAL microbiota transplantation , *IMMUNE checkpoint inhibitors , *INDOLEAMINE 2,3-dioxygenase , *IMMUNE checkpoint proteins , *DEATH receptors - Abstract
Amelanotic melanoma (AM) is a subtype of hypomelanotic or completely amelanotic melanoma. AM is a rare subtype of melanoma that exhibits a higher recurrence rate and aggressiveness as well as worse surveillance than typical melanoma. AM shows a dysregulation of melanin production, cell cycle control, and apoptosis pathways. Knowing these pathways has an application in medicine due to targeted therapies based on the inhibiting elements of the abovementioned pathways. Therefore, we summarized and discussed AM biochemical and molecular induction pathways and personalized medicine approaches, clinical management, and future directions due to the fact that AM is relatively rare. AM is commonly misdiagnosed. Hence, the role of biomarkers is becoming significant. Nonetheless, there is a shortage of biomarkers specific to AM. BRAF, NRAS, and c-KIT genes are the main targets of therapy. However, the role of BRAF and KIT in AM varied among studies. BRAF inhibitors combined with MAK inhibitors demonstrate better results. Immune checkpoint inhibitors targeting CTLA-4 combined with a programmed death receptor 1 (PD-1) show better outcomes than separately. Fecal microbiota transplantation may overcome resistance to immune checkpoint therapy of AM. Immune-modulatory vaccines against indoleamine 2,3-dioxygenase (IDO) and PD ligand (PD-L1) combined with nivolumab may be efficient in melanoma treatment. [ABSTRACT FROM AUTHOR] more...
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- 2024
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17. The autophagy protein RUBCNL/PACER represses RIPK1 kinase-dependent apoptosis and necroptosis.
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Rojas-Rivera, Diego, Beltrán, Sebastián, Muñoz-Carvajal, Francisco, Ahumada-Montalva, Pablo, Abarzúa, Lorena, Gomez, Laura, Hernandez, Fernanda, Bergmann, Cristian A., Labrador, Luis, Calegaro-Nassif, Melissa, Bertrand, Mathieu J.M., Manque, Patricio A., and Woehlbier, Ute more...
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TUMOR necrosis factor receptors ,SMALL interfering RNA ,MESENCHYMAL stem cells ,TUMOR necrosis factors ,CELL death ,DEATH receptors ,GENE enhancers - Abstract
Mesenchymal stem cells (MSCs) are used in cell therapy; nonetheless, their application is limited by their poor survival after transplantation in a proinflammatory microenvironment. Macroautophagy/autophagy activation in MSCs constitutes a stress adaptation pathway, promoting cellular homeostasis. Our proteomics data indicate that RUBCNL/PACER (RUN and cysteine rich domain containing beclin 1 interacting protein like), a positive regulator of autophagy, is also involved in cell death. Hence, we screened MSC survival upon various cell death stimuli under loss or gain of function of RUBCNL. MSCs were protected from TNF (tumor necrosis factor)-induced regulated cell death when RUBCNL was expressed. TNF promotes inflammation by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We determine that MSCs succumb to RIPK1 kinase-dependent apoptosis upon TNF sensing and necroptosis when caspases are inactivated. We show that RUBCNL is a negative regulator of both RIPK1-dependent apoptosis and necroptosis. Furthermore, RUBCNL mutants that lose the ability to regulate autophagy, retain their function in negatively regulating cell death. We also found that RUBCNL forms a complex with RIPK1, which disassembles in response to TNF. In line with this finding, RUBCNL expression limits assembly of RIPK1-TNFRSF1A/TNFR1 complex I, suggesting that complex formation between RUBCNL and RIPK1 represses TNF signaling. These results provide new insights into the crosstalk between the RIPK1-mediated cell death and autophagy machineries and suggest that RUBCNL, due to its functional duality in autophagy and apoptosis/necroptosis, could be targeted to improve the therapeutic efficacy of MSCs. Abbreviations: BAF: bafilomycin A
1 ; CASP3: caspase 3; Caspases: cysteine-aspartic proteases; cCASP3: cleaved CASP3; CQ: chloroquine; CHX: cycloheximide; cPARP: cleaved poly (ADP-ribose) polymerase; DEPs: differential expressed proteins; ETO: etoposide; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain-like; MSC: mesenchymal stem cell; MTORC1: mechanistic target of rapamycin kinase complex 1; Nec1s: necrostatin 1s; NFKB/NF-kB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PLA: proximity ligation assay; RCD: regulated cell death; RIPK1: receptor (TNFRSF)-interacting serine-threonine kinase 1; RIPK3: receptor-interacting serine-threonine kinase 3; RUBCNL/PACER: RUN and cysteine rich domain containing beclin 1 interacting protein like; siCtrl: small interfering RNA nonsense; siRNA: small interfering RNA; TdT: terminal deoxynucleotidyl transferase; Tm: tunicamycin; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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18. Apoptotic Receptors and CD107a Expression by NK Cells in an Interaction Model with Trophoblast Cells
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Valentina A. Mikhailova, Dmitry I. Sokolov, Polina V. Grebenkina, Dmitry O. Bazhenov, Igor P. Nikolaenkov, Igor Yu. Kogan, and Areg A. Totolian
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NK cells ,death receptors ,decoy receptors ,TRAIL ,Fas ,FasL ,Biology (General) ,QH301-705.5 - Abstract
Natural killer cells (NK cells) exert cytotoxicity towards target cells in several ways, including the expression of apoptosis-mediating ligands (TRAIL, FasL). In addition, NK cells themselves may be susceptible to apoptosis due to the expression of TRAIL receptors. These receptors include TRAIL-R1 (DR4), TRAIL-R2 (DR5), capable of inducing apoptosis, and TRAIL-R3 (DcR1), TRAIL-R4 (DcR2), the so-called “decoy receptors”, which lack an intracellular domain initiating activation of caspases. Of particular interest is the interaction of uterine NK cells with cells of fetal origin, trophoblasts, which are potential targets for natural killer cells to carry out cytotoxicity. The aim of this work was to evaluate the expression of proapoptotic receptors and their ligands as well as CD107a expression by NK cells in a model of interaction with trophoblast cells. To evaluate NK cells, we used cells of the NK-92 line; cells of the JEG-3 line were used as target cells. The cytokines IL-1β, IL-15, IL-18, TNFα, IL-10, TGFβ and conditioned media (CM) of the first and third trimester chorionic villi explants were used as inducers. We established that cytokines changed the expression of apoptotic receptors by NK cells: in the presence of TNFα, the amount and intensity of Fas expression increased, while in the presence of TGFβ, the amount and intensity of expression of the DR5 receptor decreased. Soluble chorionic villi factors alter the expression of TRAIL and FasL by NK-92 cells, which can reflect the suppression of the TRAIL-dependent mechanism of apoptosis in the first trimester and stimulating the Fas-dependent mechanism in the third trimester. In the presence of trophoblast cells, the expression of TRAIL and DcR1 by NK cells was reduced compared to intact cells, indicating an inhibitory effect of trophoblast cells on NK cell cytotoxicity. In the presence of chorionic villi CM and trophoblast cells, a reduced number of NK-92 cells expressing DR4 and DR5 was found. Therefore, soluble factors secreted by chorionic villi cells regulate the resistance of NK cells to death by binding TRAIL, likely maintaining their activity at a certain level in case of contact with trophoblast cells. more...
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- 2024
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19. Targeting caspase-8/c-FLIPL heterodimer in complex II promotes DL-mediated cell death.
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Hillert-Richter, Laura K., König, Corinna, Ivanisenko, Nikita V., Reinhold, Dirk, and Lavrik, Inna N.
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ACUTE myeloid leukemia ,CELL death ,DEATH receptors ,SMALL molecules ,COLON cancer ,HETERODIMERS - Abstract
Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIP
L heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIPL heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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20. Targeting caspase-8/c-FLIP L heterodimer in complex II promotes DL-mediated cell death.
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Hillert-Richter, Laura K., König, Corinna, Ivanisenko, Nikita V., Reinhold, Dirk, and Lavrik, Inna N.
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ACUTE myeloid leukemia ,CELL death ,DEATH receptors ,SMALL molecules ,COLON cancer ,HETERODIMERS - Abstract
Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIP L heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIP L heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks [ABSTRACT FROM AUTHOR] more...
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- 2024
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21. The Effect of Semaglutide on Mortality and COVID-19–Related Deaths: An Analysis From the SELECT Trial.
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Scirica, Benjamin M., Lincoff, A. Michael, Lingvay, Ildiko, Bogdanski, Pawel, Buscemi, Silvio, Colhoun, Helen, Craciun, Anca-Elena, Ezhov, Marat, Hardt-Lindberg, Søren, Kleist Jeppesen, Ole, Matos, Ana Laura S.A., Node, Koichi, Schiele, Francois, Toplak, Hermann, van Beek, André, Weeke, Peter E., Wiviott, Stephen D., Deanfield, John, and Ryan, Donna more...
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COVID-19 pandemic , *DEATH receptors , *CARDIAC arrest , *BODY mass index , *SEMAGLUTIDE - Abstract
Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk. This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19). The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants ≥45 years of age with a body mass index ≥27 kg/m2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively. Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19–related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death. Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597) [ABSTRACT FROM AUTHOR] more...
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- 2024
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22. Dichloroacetate reduces cisplatin-induced apoptosis by inhibiting the JNK/14-3-3/Bax/caspase-9 pathway and suppressing caspase-8 activation via cFLIP in murine tubular cells.
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Kimura, Hideki, Kamiyama, Kazuko, Imamoto, Toru, Takeda, Izumi, Kobayashi, Mamiko, Takahashi, Naoki, Kasuno, Kenji, Sugaya, Takeshi, and Iwano, Masayuki
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PYRUVATE dehydrogenase kinase , *DEATH receptors , *CASPASES , *OXIDATIVE phosphorylation , *DAMAGES (Law) - Abstract
Cisplatin-induced injury to renal proximal tubular cells stems from mitochondrial damage-induced apoptosis and inflammation. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, a potential generator of ROS and ATP, protects against cisplatin-induced nephrotoxicity by promoting the TCA cycle. However, its effects on apoptotic pathways and ROS production in renal tubular cells remain unclear. Here, we investigated the detailed molecular mechanisms of the DCA's effects by immunoblot, RT-PCR, RNA-sequencing, and RNA-silencing in a murine renal proximal tubular (mProx) cell line and mouse kidneys. In mProx cells, DCA suppressed cisplatin-induced apoptosis by attenuating the JNK/14-3-3/Bax/caspase-9 and death receptor/ligand/caspase-8 pathways without impeding inflammatory signaling. RNA-sequencing demonstrated that DCA increased the cisplatin-reduced expression of cFLIP, a caspase-8 inactivator, and decreased the expression of almost all oxidative phosphorylation (OXPHOS) genes. DCA also increased NF-kB activation and ROS production, probably enhancing the cFLIP induction and OXPHOS gene reduction, respectively. Furthermore, cFLIP silencing weakened the DCA's anti-apoptotic effects. Finally, in mouse kidneys, DCA attenuated cisplatin-caused injuries such as functional and histological damages, caspase activation, JNK/14-3-3 activation, and cFLIP reduction. Conclusively, DCA mitigates cisplatin-induced nephrotoxicity by attenuating the JNK/14-3-3/Bax/caspase-9 pathway and inhibiting the caspase-8 pathways via cFLIP induction, probably outweighing the cisplatin plus DCA-derived cytotoxic effects including ROS. [ABSTRACT FROM AUTHOR] more...
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- 2024
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23. Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.
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Yang, Chao-Yu, Tseng, Yi-Chun, Tu, Yi-Fan, Kuo, Bai-Jiun, Hsu, Li-Chung, Lien, Chia-I, Lin, You-Sheng, Wang, Yin-Ting, Lu, Yen-Chen, Su, Tsung-Wei, Lo, Yu-Chih, and Lin, Su-Chang
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DEATH receptors ,CASPASES ,CELLULAR signal transduction ,MUTAGENESIS ,APOPTOSIS - Abstract
cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions. FADD binds Casp-8 and then cFLIP to form the FADD-Casp8-cFLIP complex. The authors found that the DED complex could assemble in reverse order, where cFLIP oligomerizes to bind Casp-8. The resultant complex could bind FADD, generating the cFLIP-Casp-8-FADD complex by a different mechanism. [ABSTRACT FROM AUTHOR] more...
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- 2024
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24. Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor: a randomized double-blind trial.
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Cuicui Zhang, Tianqing Chu, Qiming Wang, Ying Cheng, Yongxiang Zhang, Ruili Wang, Leilei Ma, Chaonan Qian, Baohui Han, and Kai Li
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NON-small-cell lung carcinoma , *DEATH receptors , *ENDOTHELIAL cells , *ANLOTINIB , *NEOVASCULARIZATION inhibitors - Abstract
Objective: The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacypredicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. Methods: PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator's brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. Results: Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR)10 mg = 0.390 (95% confidence interval {CI}, 0.201-0.756), P = 0.005; HR12 mg = 0.397 (0.208-0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR10 mg = 0.445 (0.210-0.939), P = 0.034; HR12 mg = 0.369 (0.174-0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR10 mg = 0.340 (0.156-0.742), P = 0.007; HR12 mg = 0.340 (0.159-0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. Conclusions: Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy. [ABSTRACT FROM AUTHOR] more...
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- 2024
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25. The role of programmed death receptor (PD‐)1/PD‐ligand (L)1 in periodontitis and cancer.
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Groeger, Sabine and Meyle, Joerg
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IMMUNE checkpoint proteins , *DEATH receptors , *EPITHELIAL cells , *CANCER cells , *SQUAMOUS cell carcinoma - Abstract
The programmed‐death‐ligand‐1 (PD‐L1) is an immune‐modulating molecule that is constitutively expressed on various immune cells, different epithelial cells and a multitude of cancer cells. It is a costimulatory molecule that may impair T‐cell mediated immune response. Ligation to the programmed‐death‐receptor (PD)‐1, on activated T‐cells and further triggering of the related signaling pathways can induce T‐cells apoptosis or anergy. The upregulation of PD‐L1 in various cancer types, including oral squamous cell carcinomas, was demonstrated and has been linked to immune escape of tumors and poor prognosis. A bidirectional relationship exists between the increased PD‐L1 expression and periodontitis as well as the epithelial–mesenchymal transition (EMT), a process of interconversion of epithelial cells to mesenchymal cells that may induce immune escape of tumors. Interaction between exosomal PD‐L1 and PD‐1 on T‐cells may cause immunosuppression by blocking the activation and proliferation of T‐cells. The efficacy and importance of treatment with PD‐1/PD‐L1 checkpoint inhibitors and their prognostic influence on human cancers was demonstrated. Regarding PD‐1/PD‐L1 checkpoint inhibitors, resistances exist or may develop, basing on various factors. Further investigations of the underlying mechanisms will help to overcome the therapeutic limitations that result from resistances and to develop new strategies for the treatment of cancer. [ABSTRACT FROM AUTHOR] more...
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- 2024
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26. STAMBP is Required for Long-Term Maintenance of Neural Progenitor Cells Derived from hESCs.
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Zhang, Jitian, Zhang, Yanqi, Liu, Yancai, Zhou, Tiancheng, Pan, Guangjin, He, Jufang, and Shu, Xiaodong
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HUMAN embryonic stem cells , *PROGENITOR cells , *DEATH receptors , *CELL death , *DEVELOPMENTAL delay - Abstract
Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro. [ABSTRACT FROM AUTHOR] more...
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- 2024
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27. Association between programmed cell death ligand-1 expression in patients with cervical cancer and apparent diffusion coefficient values: a promising tool for patient´s immunotherapy selection.
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Liu, Kaihui, Yang, Wei, Tian, Haiping, Li, Yunxia, and He, Jianli
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DIFFUSION magnetic resonance imaging , *APOPTOSIS , *RECEIVER operating characteristic curves , *LIGANDS (Biochemistry) , *DEATH receptors - Abstract
Objective: To investigate the associations between apparent diffusion coefficient (ADC) values extracted from three different region of interest (ROI) position approaches and programmed cell death ligand-1 (PD-L1) expression, and evaluate the performance of the nomogram established based on ADC values and clinicopathological parameters in predicting PD-L1 expression in cervical cancer (CC) patients. Methods: Through retrospective recruitment, a training cohort of 683 CC patients was created, and a validation cohort of 332 CC patients was prospectively recruited. ROIs were delineated using three different methods to measure the mean ADC (ADCmean), single-section ADC (ADCss), and the minimum ADC of tumors (ADCmin). Logistic regression was employed to identify independent factors related to PD-L1 expression. A nomogram was drawn based on ADC values combined with clinicopathological features, its discrimination and calibration performances were estimated using the area under the curve (AUC) of receiver operating characteristic and calibration curve. The clinical benefits were evaluated by decision curve analysis. Results: The ADCmin independently correlated with PD-L1 expression. The nomogram constructed with ADCmin and other independent clinicopathological-related factors: FIGO staging, pathological grade, parametrial invasion, and lymph node status demonstrated excellent diagnostic performance (AUC = 0.912 and 0.903, respectively), good calibration capacities, and greater net benefits compared to the clinicopathological model in both the training and validation cohorts. Conclusion: ADCmin independently correlated PD-L1 expression, and the nomogram established with ADCmin and clinicopathological independent prognostic factors had a strong predictive performance for PD-L1 expression, thereby serving as a promising tool for selecting cases eligible for immunotherapy. Clinical relevance statement: The minimum ADC can serve as a reliable imaging biomarker related to PD-L1 expression; the established nomogram combines the minimum ADC and clinicopathological factors that can assist clinical immunotherapy decisions. Key Points: Diffusion-weighted imaging quantitative parameters can characterize the internal characteristics of tumor tissue. The minimum ADC significantly correlated with programmed cell death ligand-1 expression. The proposed nomogram can assist clinicians with immunotherapy decision-making for patients with CC. [ABSTRACT FROM AUTHOR] more...
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- 2024
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28. Induced Necroptosis and Its Role in Cancer Immunotherapy.
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Zhang, Ziyao, Zhang, Fangming, Xie, Wenjing, Niu, Yubo, Wang, Haonan, Li, Guofeng, Zhao, Lingyun, Wang, Xing, and Xie, Wensheng
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RECEPTOR-interacting proteins , *CYTOTOXIC T cells , *CELL death , *DEATH receptors , *DENDRITIC cells - Abstract
Necroptosis is a type of regulated cell death (RCD) that is triggered by changes in the extracellular or intracellular milieu that are picked up by certain death receptors. Thanks to its potent capacity to induce immunological responses and overcome apoptotic resistance, it has garnered significant attention as a potential cancer treatment. Basic information for the creation of nano-biomedical treatments is provided by studies on the mechanisms underlying tumor necroptosis. Receptor-interacting protein kinase 1 (RIPK1)–RIPK3-mediated necroptosis, Toll-like receptor domain-containing adapter-inducing interferon (IFN)-β (TRIF)–RIPK3-mediated necroptosis, Z-DNA-binding protein 1 (ZBP1)–RIPK3-mediated necroptosis, and IFNR-mediated necroptosis are the four signaling pathways that collectively account for triggered necroptosis in this review. Necroptosis has garnered significant interest as a possible cancer treatment strategy because, in contrast to apoptosis, it elicits immunological responses that are relevant to therapy. Thus, a thorough discussion is held on the connections between tumor cell necroptosis and the immune environment, cancer immunosurveillance, and cells such as dendritic cells (DCs), cytotoxic T cells, natural killer (NK) cells, natural killer T (NKT) cells, and their respective cytokines. Lastly, a summary of the most recent nanomedicines that cause necroptosis in order to cause immunogenic cell death is provided in order to emphasize their promise for cancer immunotherapy. [ABSTRACT FROM AUTHOR] more...
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- 2024
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29. Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer.
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Di Federico, A., Alden, S.L., Smithy, J.W., Ricciuti, B., Alessi, J.V., Wang, X., Pecci, F., Lamberti, G., Gandhi, M.M., Vaz, V.R., Spurr, L.F., Sholl, L.M., Pfaff, K.L., Rodig, S.J., Li, Y.Y., Cherniack, A.D., Nishino, M., Johnson, B.E., and Awad, M.M. more...
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NON-small-cell lung carcinoma , *IMMUNE checkpoint inhibitors , *DEATH receptors , *PROGRAMMED death-ligand 1 , *PROGRESSION-free survival - Abstract
Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ −50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274 , PDCD1LG2 , and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible. • Intrapatient paired PD-L1 TPS and TMB assessments have good concordance. • Variations in PD-L1 TPS and TMB with clinical implications may occur. • Intervening ICI therapy is associated with decrease in PD-L1 TPS. • Copy number loss in CD274 , PDCD1LG2 , and JAK2 genes are strongly associated with major decrease in PD-L1 TPS (−50% to −100%). • Variations in PD-L1 TPS and TMB have significant impact on outcomes to a subsequent ICI-based therapy. [ABSTRACT FROM AUTHOR] more...
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- 2024
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30. Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR‐T‐Cell Therapy.
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Zhang, Zhanna, Su, Manqi, Jiang, Panruo, Wang, Xiaoxia, Tong, Xiangmin, and Wu, Gongqiang
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SUPPRESSOR cells , *TREATMENT effectiveness , *CHIMERIC antigen receptors , *DEATH receptors , *CELL receptors - Abstract
Background: Chimeric antigen receptor (CAR)‐T‐cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients. Objectives: This review critically examines the challenges associated with CAR‐T‐cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance. Methods: We explore various strategies to sensitize tumor cells to CAR‐T‐cell‐mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl‐1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti‐apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti‐apoptotic protein expression, such as Bcl‐2, which may counteract CAR‐T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR‐T cell function and propose dual‐targeting CAR‐T cells to simultaneously address both myeloid‐derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS‐STING pathway, thereby improving CAR‐T cell infiltration into the tumor. Conclusions: This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR‐T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR‐T cell therapies. [ABSTRACT FROM AUTHOR] more...
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- 2024
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31. Potential Role of Tarantula Venom Peptides in Targeting Human Death Receptors: A Computational Study.
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Quiambao, Janus Isaiah R., Fowler, Peter Matthew Paul T., and Tayo, Lemmuel L.
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DEATH receptors ,CANCER cell proliferation ,MOLECULAR docking ,SPIDER venom ,VENOM ,TARANTULAS - Abstract
Featured Application: The application of this study is all computational studies considering venom peptides as potential sources of therapeutics. Animal venom has been gaining traction as a potential source of therapeutics for various diseases. Spiders encompass a wide variety of venom-producing species, of which tarantulas of the family Theraphosidae are widely known across the globe. Research towards tarantula venom therapeutics has led to its potential application as antinociceptives. Death receptors are cellular receptors that induce apoptosis—the body's natural suicide mechanism—to destroy malfunctioning cells. These are particularly of interest in cancer research, as this mechanism is tampered with, resulting in cancer cell proliferation. In this study, the viability of venom toxins from the Theraphosidae family of spiders to induce apoptosis by binding to human death receptors is investigated by carrying out anti-cancer screening, molecular docking, ADMET evaluation, then molecular dynamics and thermodynamic analysis twice, first to ascertain the best receptor–peptide systems per receptor, and secondly to more comprehensively describe binding stability and thermodynamics. Results point to favorable receptor–peptide interactions due to similarities in equilibrium behavior with the death ligand–death receptor systems, along with favorable end-state binding energies and ADMET analysis results. Further inquiry is recommended to assess the real-life efficacy and viability of theraphotoxins as apoptosis therapeutics and further improve on their ability to induce apoptosis. [ABSTRACT FROM AUTHOR] more...
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- 2024
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32. Strong activation of p53 by actinomycin D and nutlin-3a overcomes the resistance of cancer cells to the pro-apoptotic activity of the FAS ligand.
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Łasut-Szyszka, Barbara, Gdowicz-Kłosok, Agnieszka, Krześniak, Małgorzata, Głowala-Kosińska, Magdalena, Będzińska, Agnieszka, and Rusin, Marek
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DACTINOMYCIN ,DEATH receptors ,CELL receptors ,CANCER cells ,CASPASES - Abstract
The FAS ligand (FASLG) is expressed on lymphocytes, which employ it to activate death receptors on target cells. Cancer cells are generally resistant to apoptosis triggered by FASLG. In this work, we found a way to circumvent this resistance by treatment with actinomycin D (ActD) and nutlin-3a (Nut3a). We selected this drug combination based on our transcriptomic data showing strong activation of proapoptotic genes, including those for receptor-mediated apoptosis, in cells exposed to actinomycin D and nutlin-3a. To test our hypothesis, we pre-exposed cancer cell lines to this drug combination for 45 h and then treated them with recombinant FASLG. This almost instantaneously killed most cells. Actinomycin D and nutlin-3a strongly cooperated in the sensitization because the effect of the drugs acting solo was not as spectacular as the drug combination, which together with FASLG killed more than 99% of cells. Based on the caspase activation pattern (caspase-8, caspase-9, caspase-10), we conclude that both extrinsic and intrinsic pro-apoptotic pathways were engaged. In engineered p53-deficient cells, this pro-apoptotic effect was completely abrogated. Therefore, the combination of ActD + Nut3a activates p53 in an extraordinary way, which overcomes the resistance of cancer cells to apoptosis triggered by FASLG. Interestingly, other combinations of drugs, e.g., etoposide + nutlin-3a, actinomycin D + RG7112, and actinomycin D + idasanutlin had a similar effect. Moreover, normal human fibroblasts are less sensitive to death induced by ActD + Nut3a + FASLG. Our findings create the opportunity to revive the abandoned attempts of cancer immunotherapy employing the recombinant FAS ligand. [ABSTRACT FROM AUTHOR] more...
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- 2024
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33. Microglia either promote or restrain TRAIL-mediated excitotoxicity caused by Aβ1−42 oligomers.
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Zou, Jian, McNair, Elizabeth, DeCastro, Sagan, Lyons, Scott P., Mordant, Angie, Herring, Laura E., Vetreno, Ryan P., and Coleman Jr, Leon G.
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MACROPHAGE colony-stimulating factor , *TRAIL protein , *ALZHEIMER'S disease , *DEATH receptors , *DESIGNER drugs - Abstract
Background: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. Methods: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1−42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs. Results: Neurotoxicity induced by soluble Aβ1−42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. Conclusion: Microglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity. [ABSTRACT FROM AUTHOR] more...
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- 2024
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34. Expression of Apoptosis, Autophagy and Necroptosis Effectors in Rat Hippocampal Cells after Excessive Fluoride Intake.
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Nadei, O. V. and Agalakova, N. I.
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PROTEIN kinases , *AMP-activated protein kinases , *LABORATORY rats , *CASPASES , *AUTOPHAGY , *DEATH receptors - Abstract
The expression of apoptosis, autophagy and necroptosis markers in rat hippocampal cells after long-term intake of excessive fluoride (F–) doses was studied at transcriptional and translational levels. Male Wistar rats were divided into 4 groups given 0.4 (control), 5, 20, and 50 mg/L F– (as NaF) with drinking water over 12 months. Changes in the content of effectors of mitochondrial (Bcl-2, Bax, caspase-9, caspase-3) and receptor (caspase-8, Fas) pathways of apoptosis, mediators (Ulk-1, Beclin-1) and modulators (AMPK, Akt, mTOR) of autophagy, as well as necroptosis effectors (RIP and MLKL), were assessed by immunoblotting, while the expression of Bcl2, Bax, Casp3, Ulk1, Beclin1, Prkaa1, Akt, and mTor genes—by real-time PCR. In the hippocampus of F–-exposed animals, the expression ratio of Bcl2/Bax genes and Bcl-2/Bax proteins decreased, caspase-9 and caspase-3 were activated, but caspase-8 and Fas receptor levels remained stable. Long-term F– intake had no effect on the content of the autophagy initiator Ulk-1 and protein kinases AMPK, Akt and mTOR, but led to the inhibition of the key autophagy mediator Beclin-1. Expression levels of the necroptosis effectors RIP and MLKL in hippocampal cells of rats exposed to excessive F– doses did not change as well. Thus, long-term exposure to excessive F– was accompanied by the activation of apoptosis, mainly through the mitochondrial pathway, against the background of autophagy suppression. [ABSTRACT FROM AUTHOR] more...
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- 2024
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35. Acquired Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Resistance of Human Colorectal Cancer Cells Is Linked to Histone Acetylation and Is Synergistically Ameliorated by Combination with HDAC Inhibitors.
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Kim, Se Lim, Shin, MinWoo, Jin, Byung Chul, Seo, SeungYoung, Ha, Gi Won, and Kim, Sang Wook
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MITOGEN-activated protein kinases , *HISTONE deacetylase inhibitors , *TRAIL protein , *HISTONE acetylation , *DEATH receptors - Abstract
Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive target for the treatment of various malignancies; however, its therapeutic potential is limited because of the frequent occurrence of tumor cell resistance. In this study, we determined whether TRAIL resistance acquired by repeated administration could be overcome by HDAC inhibition in human colorectal cancer cells. Methods: TRAIL-resistant HCT116 human colorectal cancer cells (HCT116-TR) were generated by repeated treatment with 10 and 25 ng/mL TRAIL twice weekly for 28 days. Results: The resulting TRAIL-resistant cells were noncross-resistant to other chemotherapeutic agents. The levels of histone acetylation-related proteins, such as ac-histone H4 and HDAC1, were altered in HCT116-TR cells compared with the parental HCT116 cell line. The combined treatment with TRAIL and HDAC inhibitors significantly increased apoptosis in HCT116-TR cells and indicated a synergistic effect. The mechanism by which HDAC inhibition sensitizes HCT116-TR cells to TRAIL is dependent on the intrinsic pathway. In addition, we found that HDAC inhibition enhanced the sensitivity of cells to TRAIL through mitogen-activated protein kinases/CCAAT/enhancer-binding protein homologs of protein-dependent upregulation of death receptor 5. Conclusion: These results suggest that histone acetylation is responsible for acquired TRAIL resistance after repeated exposure and acquired resistance to TRAIL may be overcome by combination therapies with HDAC inhibitors. [ABSTRACT FROM AUTHOR] more...
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- 2024
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36. Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.
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Garnish, Sarah E., Horne, Christopher R., Yanxiang Meng, Young, Samuel N., Jacobsen, Annette V., Hildebrand, Joanne M., and Murphy, James M.
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APOPTOSIS , *CELL death , *CELL membranes , *DEATH receptors , *TOLL-like receptors - Abstract
Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (mixed lineage kinase domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is trafficked to the plasma membrane via the Golgi-, actin- and microtubule-machinery, where activated MLKL accumulates until a critical lytic threshold is exceeded and cell death ensues. Mechanistically, MLKL’s lytic function relies on disengagement of the N-terminal membrane-permeabilising four-helix bundle domain from the central autoinhibitory brace helix: a process that can be experimentally mimicked by introducing the R30E MLKL mutation to induce stimulus-independent cell death. Here, we screened a library of 429 kinase inhibitors for their capacity to block R30E MLKL-mediated cell death, to identify co-effectors in the terminal steps of necroptotic signalling. We identified 13 compounds — ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib, Ipatasertib, LJI308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a, Temsirolimus and Tideglusib — each of which inhibits mammalian target of rapamycin (mTOR) signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting the transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death. [ABSTRACT FROM AUTHOR] more...
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- 2024
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37. Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers : the "all-around warrior" in immunotherapy.
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Liu, Qiang, Guan, Yujing, and Li, Shenglong
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PROGRAMMED death-ligand 1 , *PROGRAMMED cell death 1 receptors , *RENAL cell carcinoma , *DEATH receptors , *POST-translational modification - Abstract
Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR] more...
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- 2024
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38. Modulation of extrinsic apoptotic pathway by intracellular glycosylation.
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Seyrek, Kamil, Ivanisenko, Nikita V., König, Corinna, and Lavrik, Inna N.
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BACTERIAL proteins , *DEATH receptors , *HYDROXYL group , *CELL death , *COLONIZATION (Ecology) , *POST-translational modification - Abstract
O-GlcNAcylation of intracellular proteins takes place via a single transfer of GlcNAc to the hydroxyl group of serine or threonine residues. O-GlcNAcylation modulates the extrinsic apoptotic pathway. To facilitate colonization of pathogens in host cells, bacterial effector proteins suppress death receptor (DR) signaling. Sustained increases in O-GlcNAcylation contribute to tumor development. The importance of post-translational modifications (PTMs), particularly O-GlcNAcylation, of cytoplasmic proteins in apoptosis has been neglected for quite a while. Modification of cytoplasmic proteins by a single N-acetylglucosamine sugar is a dynamic and reversible PTM exhibiting properties more like phosphorylation than classical O- and N-linked glycosylation. Due to the sparse information existing, we have only limited understanding of how GlcNAcylation affects cell death. Deciphering the role of GlcNAcylation in cell fate may provide further understanding of cell fate decisions. This review focus on the modulation of extrinsic apoptotic pathway via GlcNAcylation carried out by O-GlcNAc transferase (OGT) or by other bacterial effector proteins. [ABSTRACT FROM AUTHOR] more...
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- 2024
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39. Construction and validation of a synthetic phage-displayed nanobody library.
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Minju Kim, Xuelian Bai, Hyewon Im, Jisoo Yang, Youngju Kim, Minjoo MJ Kim, Yeonji Oh, Yuna Jeon, Hayoung Kwon, Seunghyun Lee, and Chang-Han Lee
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PEPTIDES , *SYNTHETIC antibodies , *IMMUNOGLOBULINS , *FRAMESHIFT mutation , *DEATH receptors - Abstract
Nanobodies derived from camelids and sharks offer unique advantages in therapeutic applications due to their ability to bind to epitopes that were previously inaccessible. Traditional methods of nanobody development face challenges such as ethical concerns and antigen toxicity. Our study presents a synthetic, phagedisplayed nanobody library using trinucleotide-directed mutagenesis technology, which allows precise amino acid composition in complementarity-determining regions (CDRs), with a focus on CDR3 diversity. This approach avoids common problems such as frameshift mutations and stop codon insertions associated with other synthetic antibody library construction methods. By analyzing FDA-approved nanobodies and Protein Data Bank sequences, we designed sub-libraries with different CDR3 lengths and introduced amino acid substitutions to improve solubility. The validation of our library through the successful isolation of nanobodies against targets such as PD-1, ATXN1 and STAT3 demonstrates a versatile and ethical platform for the development of high specificity and affinity nanobodies and represents a significant advance in biotechnology. [ABSTRACT FROM AUTHOR] more...
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- 2024
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40. Picornavirus VP3 protein induces autophagy through the TP53-BAD-BAX axis to promote viral replication.
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Mao, Ruoqing, Zhu, Zixiang, Yang, Fan, Sun, Dehui, Zhou, Xiaoli, Cao, Weijun, Qin, Xiaodong, Dang, Wen, Liu, Huanan, Tian, Hong, Zhang, Keshan, Wu, Qingfeng, Liu, Xiangtao, and Zheng, Haixue
- Subjects
VIRAL replication ,AUTOPHAGY ,TUMOR proteins ,P53 protein ,FOOT & mouth disease ,VIRUS diseases ,DEATH receptors - Abstract
Macroautophagy/autophagy and apoptosis are pivotal interconnected host cell responses to viral infection, including picornaviruses. Here, the VP3 proteins of picornaviruses were determined to trigger autophagy, with the autophagic flux being triggered by the TP53-BAD-BAX axis. Using foot-and-mouth disease virus (FMDV) as a model system, we unraveled a novel mechanism of how picornavirus hijacks autophagy to bolster viral replication and enhance pathogenesis. FMDV infection induced both autophagy and apoptosis in vivo and in vitro. FMDV VP3 protein facilitated the phosphorylation and translocation of TP53 from the nucleus into the mitochondria, resulting in BAD-mediated apoptosis and BECN1-mediated autophagy. The amino acid Gly129 in VP3 is essential for its interaction with TP53, and crucial for induction of autophagy and apoptosis. VP3-induced autophagy and apoptosis are both essential for FMDV replication, while, autophagy plays a more important role in VP3-mediated pathogenesis. Mutation of Gly129 to Ala129 in VP3 abrogated the autophagic regulatory function of VP3, which significantly decreased the viral replication and pathogenesis of FMDV. This suggested that VP3-induced autophagy benefits viral replication and pathogenesis. Importantly, this Gly is conserved and showed a common function in various picornaviruses. This study provides insight for developing broad-spectrum antivirals and genetic engineering attenuated vaccines against picornaviruses. Abbreviations: 3-MA, 3-methyladenine; ATG, autophagy related; BAD, BCL2 associated agonist of cell death; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X, apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCL2, BCL2 apoptosis regulator; BID, BH3 interacting domain death agonist; BIP-V5, BAX inhibitor peptide V5; CFLAR/FLIP, CASP8 and FADD like apoptosis regulator; CPE, cytopathic effects; CQ, chloroquine; CV, coxsackievirus; DAPK, death associated protein kinase; DRAM, DNA damage regulated autophagy modulator; EV71, enterovirus 71; FMDV, foot-and-mouth disease virus; HAV, hepatitis A virus; KD, knockdown; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MOI, multiplicity of infection; MTOR, mechanistic target of rapamycin kinase; PML, promyelocytic leukemia; PV, poliovirus; SVA, Seneca Valley virus; TCID50, 50% tissue culture infectious doses; TOR, target of rapamycin. TP53/p53, tumor protein p53; WCL, whole-cell lysate. [ABSTRACT FROM AUTHOR] more...
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- 2024
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41. Multiple mechanisms contribute to acquired TRAIL resistance in multiple myeloma.
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Ticona-Pérez, Fany V., Chen, Xi, Pandiella, Atanasio, and Díaz-Rodríguez, Elena
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PEPTIDES , *DEATH receptors , *CELL death , *CANCER cells , *MULTIPLE myeloma - Abstract
Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance. [ABSTRACT FROM AUTHOR] more...
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- 2024
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42. Analysis of efficacy and safety for the combination of tislelizumab and regorafenib in advanced hepatocellular carcinoma: A prospective clinical study.
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Sun, Pengfei, Zhang, Ying, Tian, Shilin, Cui, Kai, Zhong, Jingtao, Zhang, Chengsheng, Wang, Dongxu, Zhang, Bo, Shi, Xuetao, and Li, Zhongchao
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ADVERSE health care events , *DEATH receptors , *HEPATOCELLULAR carcinoma , *PROGRESSION-free survival , *REGORAFENIB - Abstract
Backgrounds: Programmed death receptor 1 (PD-1) monoclonal antibody has been approved for the first and second-line treatments of hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of tislelizumab + regorafenib as a second-line treatment option for advanced HCC. Methods: Treatment-related adverse events (TRAEs) were the primary endpoints in this clinical trial comprising 28 patients with advanced HCC. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: According to the mRECIST 1.1 evaluation criteria, the ORR was 28.6%. Complete and partial response were observed in 3 and 5 patients, respectively; stable disease was observed in 12 patients (DCR, 71.4%). The median PFS was 6.4 months. The incidence of grade 1–2 and 3–4 TRAEs was 57.1% and 39.3%, respectively. Conclusion: This study suggests that tislelizumab + regorafenib can be used as a second-line treatment for advanced HCC. [ABSTRACT FROM AUTHOR] more...
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- 2024
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43. PD-1/PD-L1 信号通路在脓毒症不同器官免疫调控中的研究进展.
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张登容, 刘春瑶, 婷婷, 罗镇颉, 龙仙萍, and 汪松
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IMMUNOSUPPRESSION , *DEATH receptors , *PROGRAMMED cell death 1 receptors , *PROGRAMMED death-ligand 1 , *SEPSIS - Abstract
Sepsis is a life-threatening organ dysfunction caused by the imbalance of host immune response to infection, which immune regulation mechanism is complex and has not been clarified. Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) is a negative co-inhibitory molecule that has attracted much attention in recent years. Studies have shown that PD-1/PD-L1 signaling pathway plays an important immunosuppressive role in sepsis. There are differences in immune regulation mechanisms in heart, liver, spleen, lung and kidney, which has not been clarified. Immune regulation of PD-1/PD-L1 in different organs of sepsis is reviewied in this article, which could to provide a new direction for the study of sepsis. [ABSTRACT FROM AUTHOR] more...
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- 2024
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44. Research Progress of Necroptosis in Digestive Diseases.
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Xiaojing WEI, Binjing ZHAO, Xinyi JIANG, and Rui WANG
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DIGESTIVE system diseases , *DEATH receptors , *DIGESTIVE organs , *PROTEIN receptors , *CELL death - Abstract
Digestive system diseases refer to organic and functional disorders of the digestive system, which are prone to recurrence and frequently accompanied by multiple complications. Necroptosis is a regulated mode of cell death mediated by death receptors, dependent on receptor protein activation, and could be specifically inhibited by necrostatin-1. Necroptosis is involved in pathological and physiological processes of various diseases, and plays an important role in the growth and development of organisms and the homeostasis of organ tissues. This paper reviewed the research advancement of necroptosis in digestive system disorders, and discussed the relationship between necroptosis and digestive system diseases, aiming to provide theoretical basis for the cure of these diseases. [ABSTRACT FROM AUTHOR] more...
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- 2024
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45. SH003 Induces DR5-Mediated Caspase-Dependent Apoptosis of NSCLC Through Inhibition of AKT Survival Pathway.
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Ji Hye Kim, Sooyeon Kang, Gyu-Ri Lee, and Seong-Gyu Ko
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NON-small-cell lung carcinoma , *ASTRAGALUS membranaceus , *WESTERN immunoblotting , *DEATH receptors , *CELL analysis - Abstract
Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is well known to selectively induce apoptotic cell death in cancer cells, not in normal cells, with death receptors (DRs)—DR4 and DR5. In consequence of this specialty, this cytokine and its receptors are considered for candidates of target therapy in clinic. SH003, a new traditional medicine-based polyherbal preparation, consists of Astragalus membranaceus (Am), Angelica gigas (Ag) and Trichosanthes kirilowii Maximowicz (Tk). In this study, we investigated whether SH003 can induce apoptosis through DRs in non-small-cell lung cancer (NSCLC) cells. Methods: Cell proliferation and cytotoxicity were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic assay, and, trypan blue exclusion staining, protein expression by western blot analysis, and apoptosis by fluorescence-activated cell sorting analysis. Results: We found that SH003-induced apoptosis in NSCLC cells through several mechanisms. First of all, MTT and colony formation assay confirmed the growth-inhibitory effect of SH003 in H460 cells. Second, SH003 upregulated the expression of DR4 and DR5. Third, it activated caspase-8, caspase-7, and caspase-3 cascades, which are essential for DR-mediated extrinsic apoptosis. The effect of SH003-induced apoptosis was significantly abolished by inhibition of caspases enzymes. And also, SH003 cleaved caspse-9. Fourth, SH003 reduced AKT kinase phosphorylation, and overexpression of AKT abrogated the caspase-dependent apoptosis by SH003. Fifth, SH003 inactivated ERK, but, constitutive ERK expression did not completely reduce SH003-mediated growth inhibition and apoptosis. Conclusions: SH003 potentiates caspase-dependent apoptosis of NSCLC through the upregulation of DRs, activation of caspase cascades and downregulation of AKT cell survival pathways. [ABSTRACT FROM AUTHOR] more...
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- 2024
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46. Predictive Value of Lymphocyte‐to‐Neutrophil Ratio and Platelet‐to‐Neutrophil Ratio on PD‐L1 Expression in Lung Cancer.
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Cui, Shun‐Shun, Shen, Ya, and Yang, Rui‐Qing
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LOGISTIC regression analysis , *RECEIVER operating characteristic curves , *DEATH receptors , *UNIVARIATE analysis , *LUNG cancer - Abstract
Objective: This study aimed to examine the predictive effect of the lymphocyte‐to‐neutrophil ratio (LNR) and the platelet‐to‐neutrophil ratio (PNR) on the expression of programmed death receptor ligand 1 (PD‐L1) in patients diagnosed with lung cancer. Methods: The clinical records of 86 patients diagnosed with lung cancer between January 2020 and February 2022 at Fu Yang People's Hospital were retrospectively analyzed. The records included information on age, gender, smoking history, hematological indices at the time of admission, staging of the lung malignancy, histopathological subtype, comorbidities, and the expression levels of PD‐L1. Patients were stratified into two distinct cohorts based on their PD‐L1 expression levels: Those with an expression level greater than or equal to 1% were classified into the PD‐L1 positive expression group, while the remainder were categorized as the PD‐L1 negative expression group. Univariate analysis and multivariate logistic regression analysis were used to identify the influencing factors of PD‐L1, and the diagnostic efficacy was calculated using the receiver operating characteristic (ROC) curve. Results: Upon analysis, the PD‐L1 positive expression group manifested notably lower values as compared to their counterparts in the PD‐L1 negative expression group (LNR: 0.262 ± 0.105 vs. 0.390 ± 0.201; PNR: 41.03 [29.64, 50.11] vs. 49.50 [37.38, 73.83]), and these differences were statistically significant. There was a notable disparity in PD‐L1 expression based on gender, with males exhibiting a statistically significant higher positivity rate compared to females. Furthermore, patients in Stages I–III of the disease demonstrated a markedly elevated PD‐L1 positivity rate compared to those in Stage IV (p < 0.05). Incorporating univariates with statistical differences into multivariate logistic regression analysis suggests that stage and LNR are independent risk factors for PD‐L1 negative expression. ROC curve analyses revealed that the area under the ROC curve (AUC) for LNR as an indicator for PD‐L1 positive expression stood at 0.706, while the AUC for PNR was calculated at 0.687. Conclusion: PD‐L1 expression is correlated with gender and lung cancer staging, and LNR and PNR have a predictive value for PD‐L1 expression. [ABSTRACT FROM AUTHOR] more...
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- 2024
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47. Prospects of compounds of herbal plants as anticancer agents: a comprehensive review from molecular pathways.
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Situmorang, Putri Cahaya, Ilyas, Syafruddin, Nugraha, Sony Eka, Syahputra, Rony Abdi, and Abd Rahman, Nik Mohd Afizan Nik
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CARCINOGENS ,BIOACTIVE compounds ,DEATH receptors ,CELL cycle ,ANTINEOPLASTIC agents ,PHYTOCHEMICALS ,BOTANICAL chemistry - Abstract
Cancer refers to the proliferation and multiplication of aberrant cells inside the human body, characterized by their capacity to proliferate and infiltrate various anatomical regions. Numerous biochemical pathways and signaling molecules have an impact on the cancer auto biogenesis process. The regulation of crucial cellular processes necessary for cell survival and proliferation, which are triggered by phytochemicals, is significantly influenced by signaling pathways. These pathways or components are regulated by phytochemicals. Medicinal plants are a significant reservoir of diverse anticancer medications employed in chemotherapy. The anticancer effects of phytochemicals are mediated by several methods, including induction of apoptosis, cessation of the cell cycle, inhibition of kinases, and prevention of carcinogenic substances. This paper analyzes the phytochemistry of seven prominent plant constituents, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins, focusing on the involvement of the MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, and actin dynamics. Hence, this review has examined a range of phytochemicals, encompassing their structural characteristics and potential anticancer mechanisms. It has underscored the significance of plant-derived bioactive compounds in the prevention of cancer, utilizing diverse molecular pathways. In addition, this endeavor also seeks to incentivize scientists to carry out clinical trials on anticancer medications derived from plants. [ABSTRACT FROM AUTHOR] more...
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- 2024
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48. TLR4 signalling in ischemia/reperfusion injury: a promising target for linking inflammation, oxidative stress and programmed cell death to improve organ transplantation outcomes.
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Sutian Wang, Kunli Zhang, Qiuyan Huang, Fanming Meng, and Shoulong Deng
- Subjects
APOPTOSIS ,TRANSPLANTATION of organs, tissues, etc. ,TOLL-like receptors ,OXIDATIVE stress ,DEATH receptors ,REPERFUSION injury - Abstract
Transplantations represent the principal therapeutic interventions for terminal organ failure, a procedure that has salvaged myriad lives annually. Ischemia/reperfusion injury (IRI) is frequently correlated with an unfavourable prognosis and is relevant for early graft dysfunction and graft survival. IRI constitutes a complex pathological state influenced by a series of factors such as oxidative stress, metabolic stress, leukocytic infiltration, programmed cell death pathways, and inflammatory immune responses. Reducing ischemia/reperfusion injury is one of the main directions of transplantation research. Toll-like receptors (TLRs) are important pattern-recognition receptors expressed on various organs that orchestrate the immune responses upon recognising PAMPs and DAMPs. Targeting the TLR4 signalling has recently been suggested as a promising approach for alleviating IRI by affecting inflammation, oxidative stress and programmed cell death (PCD). In this minireview, we summarise the role of TLR4 signalling in regulating inflammation, oxidative stress and PCD in organ transplantation and discuss their interactions during IRI. A detailed understanding of the multiple functions of TLR4 in IRI provides novel insights into developing therapies to improve organ transplantation outcomes. [ABSTRACT FROM AUTHOR] more...
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- 2024
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49. Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes.
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Hulen, Thomas Morgan, Friese, Christina, Kristensen, Nikolaj Pagh, Granhøj, Joachim Stoltenborg, Borch, Troels Holz, Peeters, Marlies J. W., Donia, Marco, Andersen, Mads Hald, Hadrup, Sine Reker, Svane, Inge Marie, and Met, Özcan more...
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TUMOR antigens ,TUMOR-infiltrating immune cells ,DEATH receptors ,GENETIC barcoding ,CELLULAR therapy - Abstract
Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity. [ABSTRACT FROM AUTHOR] more...
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- 2024
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50. Potential of Polar Lipids Isolated from the Marine Sponge Haliclona (Halichoclona) vansoesti against Melanoma.
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Ruocco, Nadia, Nuzzo, Genoveffa, Federico, Serena, Esposito, Roberta, Gallo, Carmela, Ziaco, Marcello, Manzo, Emiliano, Fontana, Angelo, Bertolino, Marco, Zagami, Giacomo, Zupo, Valerio, Sansone, Clementina, and Costantini, Maria more...
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DEATH receptors , *SPONGES (Invertebrates) , *TUMOR necrosis factor receptors , *MELANOMA , *NUCLEAR magnetic resonance , *LIPIDS - Abstract
Marine sponges represent a good source of natural metabolites for biotechnological applications in the pharmacological, cosmeceutical, and nutraceutical fields. In the present work, we analyzed the biotechnological potential of the alien species Haliclona (Halichoclona) vansoesti de Weerdt, de Kluijver & Gomez, 1999, previously collected in the Mediterranean Sea (Faro Lake, Sicily). The bioactivity and chemical content of this species has never been investigated, and information in the literature on its Caribbean counterpart is scarce. We show that an enriched extract of H. vansoesti induced cell death in human melanoma cells with an IC50 value of 36.36 µg mL−1, by (i) triggering a pro-inflammatory response, (ii) activating extrinsic apoptosis mediated by tumor necrosis factor receptors triggering the mitochondrial apoptosis via the involvement of Bcl-2 proteins and caspase 9, and (iii) inducing a significant reduction in several proteins promoting human angiogenesis. Through orthogonal SPE fractionations, we identified two active sphingoid-based lipid classes, also characterized by nuclear magnetic resonance and mass spectrometry, as the main components of two active fractions. Overall, our findings provide the first evaluation of the anti-cancer potential of polar lipids isolated from the marine sponge H. (Halichoclona) vansoesti, which may lead to new lead compounds with biotechnological applications in the pharmaceutical field. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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