Diabetes is a chronic metabolic disease that is endemic worldwide and is characterized by persistent hyperglycemia accompanied by multiple severe complications, including cardiovascular disease, kidney dysfunction, neuropathy, and retinopathy. The pathogenesis of diabetes mellitus and its complications is multifactorial, involving various molecular and cellular pathways. In recent years, research has indicated that mechanisms of cell death play a significant role in the advancement of diabetes and its complications. PANoptosis is a complex phenomenon caused by three cell death pathways: programmed apoptosis, necroptosis and pyroptosis. The contribution of PANoptosis to diabetes and its complications remains incompletely understood. Non-coding RNA, an important molecule in gene expression regulation, has shown significant regulatory functions in a variety of diseases. This paper reviews the underlying mechanisms of diverse types of non-coding RNAs (including lncRNA, miRNA and circRNA) in regulating PANoptosis and their specific contributions in diabetes, aiming to explore how non-coding RNAs influence PANoptosis and their effects in diabetes.
{"title":"Research progress of non-coding RNA regulating the role of PANoptosis in diabetes mellitus and its complications.","authors":"Guangyu Han, Kaibo Hu, Tianfeng Luo, Wenting Wang, Deju Zhang, Liu Ouyang, Xiao Liu, Jianping Liu, Yuting Wu, Jianqi Liang, Jitao Ling, Yixuan Chen, Rui Xuan, Jing Zhang, Peng Yu","doi":"10.1007/s10495-024-02066-w","DOIUrl":"https://doi.org/10.1007/s10495-024-02066-w","url":null,"abstract":"<p><p>Diabetes is a chronic metabolic disease that is endemic worldwide and is characterized by persistent hyperglycemia accompanied by multiple severe complications, including cardiovascular disease, kidney dysfunction, neuropathy, and retinopathy. The pathogenesis of diabetes mellitus and its complications is multifactorial, involving various molecular and cellular pathways. In recent years, research has indicated that mechanisms of cell death play a significant role in the advancement of diabetes and its complications. PANoptosis is a complex phenomenon caused by three cell death pathways: programmed apoptosis, necroptosis and pyroptosis. The contribution of PANoptosis to diabetes and its complications remains incompletely understood. Non-coding RNA, an important molecule in gene expression regulation, has shown significant regulatory functions in a variety of diseases. This paper reviews the underlying mechanisms of diverse types of non-coding RNAs (including lncRNA, miRNA and circRNA) in regulating PANoptosis and their specific contributions in diabetes, aiming to explore how non-coding RNAs influence PANoptosis and their effects in diabetes.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aims to investigate the in vitro antiproliferative and pro-apoptotic/apoptotic potential of active constituents of essential oils on two cancer cell lines; namely, breast adenocarcinoma (MCF-7) and urinary bladder cancer (T24). Essential oils active constituents (EO-ACs) entail a spectrum of phytochemicals with widely demonstrated anticancer potential. We assessed the effects of eight essential oils active constituents on T24 and MCF-7 cell lines in both dose- (16-1024 µg/mL) and time-dependent manners. Among these, five EO-ACs (citral, carvacrol, eugenol, geraniol, and thymol) exhibited IC50 values, ranging from 24 µg/mL to 34 µg/mL, as determined by the MTT assay over 72 h. It was observed that the mitochondrial membrane potential decreased while ROS generation increased substantially in treated cells compared to the control. The underlying apoptotic pathway with regard to pro-apoptotic/apoptotic genes was explored through qRT-PCR and western blotting, which showed significant (p < 0.05) upregulation of Bax, Bak, caspase 7, caspase 9, and downregulation of Bcl-2, pERK, and pAkt. The in-silico study showed strong interaction of thymol and carvacrol with Caspase 9, with complex binding energies of -6.1 Kcal/mol and - 6.3 Kcal/mol, respectively. In conclusion, EO-ACs, particularly thymol and carvacrol, effectively reduced cell viability, and triggered caspase-dependent apoptosis in both MCF-7 and T-24 cell lines. These findings categorically underscore EO-ACs as promising active compounds for anticancer therapy, warranting further in-depth exploration through in vivo studies.
{"title":"Molecular mechanisms of antiproliferative and pro-apoptotic effects of essential oil active constituents in MCF7 and T24 cancer cell lines: in vitro insights and in silico modelling of proapoptotic gene product-compound interactions.","authors":"Deepika Saini, Pankaj Kumar Chaudhary, Jitendra Kumar Chaudhary, Harry Kaur, Ganesh Kumar Verma, Siddhartha Das Pramanik, Partha Roy, Anissa Atif Mirza-Shariff, Ramasare Prasad","doi":"10.1007/s10495-024-02065-x","DOIUrl":"https://doi.org/10.1007/s10495-024-02065-x","url":null,"abstract":"<p><p>This study aims to investigate the in vitro antiproliferative and pro-apoptotic/apoptotic potential of active constituents of essential oils on two cancer cell lines; namely, breast adenocarcinoma (MCF-7) and urinary bladder cancer (T24). Essential oils active constituents (EO-ACs) entail a spectrum of phytochemicals with widely demonstrated anticancer potential. We assessed the effects of eight essential oils active constituents on T24 and MCF-7 cell lines in both dose- (16-1024 µg/mL) and time-dependent manners. Among these, five EO-ACs (citral, carvacrol, eugenol, geraniol, and thymol) exhibited IC<sub>50</sub> values, ranging from 24 µg/mL to 34 µg/mL, as determined by the MTT assay over 72 h. It was observed that the mitochondrial membrane potential decreased while ROS generation increased substantially in treated cells compared to the control. The underlying apoptotic pathway with regard to pro-apoptotic/apoptotic genes was explored through qRT-PCR and western blotting, which showed significant (p < 0.05) upregulation of Bax, Bak, caspase 7, caspase 9, and downregulation of Bcl-2, pERK, and pAkt. The in-silico study showed strong interaction of thymol and carvacrol with Caspase 9, with complex binding energies of -6.1 Kcal/mol and - 6.3 Kcal/mol, respectively. In conclusion, EO-ACs, particularly thymol and carvacrol, effectively reduced cell viability, and triggered caspase-dependent apoptosis in both MCF-7 and T-24 cell lines. These findings categorically underscore EO-ACs as promising active compounds for anticancer therapy, warranting further in-depth exploration through in vivo studies.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1007/s10495-024-02062-0
Latoya McGlorthan, Ana Paucarmayta, Yovanni Casablanca, G Larry Maxwell, Viqar Syed
{"title":"Retraction Note: Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro.","authors":"Latoya McGlorthan, Ana Paucarmayta, Yovanni Casablanca, G Larry Maxwell, Viqar Syed","doi":"10.1007/s10495-024-02062-0","DOIUrl":"https://doi.org/10.1007/s10495-024-02062-0","url":null,"abstract":"","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-26DOI: 10.1007/s10495-024-02052-2
Liang Qian, Ling Wu, Xiaohui Miao, Jiao Xu, Yao Zhou
The treatment of non-small cell lung cancer (NSCLC) remains a critical challenge in oncology, primarily due to the dysfunction and exhaustion of T cells within the tumor microenvironment, which greatly limits the effectiveness of immunotherapy. This study investigates the regulatory role of the T cell immunoglobulin and ITIM domain (TIGIT)-CD226-PVR signaling axis in the exhaustion and apoptosis of cluster of differentiation (CD)27+/CD127+T cells in NSCLC. Utilizing single-cell sequencing technology, we conducted a comprehensive gene expression analysis of T cells in a mouse model of NSCLC. Bioinformatics analysis revealed that the TIGIT-CD226-PVR signaling axis is highly active in the CD27+/CD127+T cell subset and is closely associated with their functional decline and exhaustion. In vitro experiments further demonstrated that inhibiting the TIGIT-PVR pathway while activating the CD226-PVR pathway significantly restored T cell proliferation and effector function. Importantly, in vivo studies showed that targeting this axis can significantly alleviate T cell exhaustion, enhance their cytotoxicity against NSCLC cells, and promote apoptosis, thereby improving the efficacy of immunotherapy.
{"title":"The role of TIGIT-CD226-PVR axis in mediating T cell exhaustion and apoptosis in NSCLC.","authors":"Liang Qian, Ling Wu, Xiaohui Miao, Jiao Xu, Yao Zhou","doi":"10.1007/s10495-024-02052-2","DOIUrl":"https://doi.org/10.1007/s10495-024-02052-2","url":null,"abstract":"<p><p>The treatment of non-small cell lung cancer (NSCLC) remains a critical challenge in oncology, primarily due to the dysfunction and exhaustion of T cells within the tumor microenvironment, which greatly limits the effectiveness of immunotherapy. This study investigates the regulatory role of the T cell immunoglobulin and ITIM domain (TIGIT)-CD226-PVR signaling axis in the exhaustion and apoptosis of cluster of differentiation (CD)27+/CD127+T cells in NSCLC. Utilizing single-cell sequencing technology, we conducted a comprehensive gene expression analysis of T cells in a mouse model of NSCLC. Bioinformatics analysis revealed that the TIGIT-CD226-PVR signaling axis is highly active in the CD27+/CD127+T cell subset and is closely associated with their functional decline and exhaustion. In vitro experiments further demonstrated that inhibiting the TIGIT-PVR pathway while activating the CD226-PVR pathway significantly restored T cell proliferation and effector function. Importantly, in vivo studies showed that targeting this axis can significantly alleviate T cell exhaustion, enhance their cytotoxicity against NSCLC cells, and promote apoptosis, thereby improving the efficacy of immunotherapy.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention. Swiss albino mice were treated with sodium arsenite (orally: 0.05 mg/L) and folic acid (orally:10 mg/kg) for 28 days. We observed that arsenic caused noticeable cell loss with morphological alterations in cerebellum, which was remarkably restored by folic acid. Arsenic-induced morphological alterations consequently perturbed transcriptional activities of neural stem cell factors-SOX2 and KLF9, which resulted in the suppression of pro-neurogenic mediators NeuroD1, Neurogenin2, calbindin and NeuN. Interestingly, folic acid reversed the expression of these critical pro-neurogenic mediators to mitigate these degenerative changes to promote neurogenesis. Delving deep, we found that folic acid rescued arsenic-exposed cerebellum from severe oxidative and pro-inflammatory insults by increasing antioxidants like SOD, Catalase, GSH, upregulating Nrf2 and downregulating M1 macrophages, JNK, NF-κB, and STAT3 activities. For the first time, we are reporting that arsenic induced a G1/S cell cycle arrest and triggered apoptosis in mouse cerebellum by activating the p53-p21 axis, downregulating CDKs and instigated p21-mediated suppression of SOX2 transcriptional activity. Folic acid abated such alterations by modulating the p53/p21/SOX2 axis. Collectively, the anti-apoptotic and pro-neurogenic effects of folic acid present it as a promising therapeutic candidate, warranting further research into its efficacy against metal-induced neurodegenerative disorders.
{"title":"Arsenic unsettles the cerebellar balance between neurodegeneration and neurogenesis: reversal by folic acid.","authors":"Ankur Das, Ankan Mitra, Swaimanti Sarkar, Sourav Ghosh, Debasish Bandyopadhyay, Sreya Chattopadhyay","doi":"10.1007/s10495-024-02054-0","DOIUrl":"https://doi.org/10.1007/s10495-024-02054-0","url":null,"abstract":"<p><p>Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention. Swiss albino mice were treated with sodium arsenite (orally: 0.05 mg/L) and folic acid (orally:10 mg/kg) for 28 days. We observed that arsenic caused noticeable cell loss with morphological alterations in cerebellum, which was remarkably restored by folic acid. Arsenic-induced morphological alterations consequently perturbed transcriptional activities of neural stem cell factors-SOX2 and KLF9, which resulted in the suppression of pro-neurogenic mediators NeuroD1, Neurogenin2, calbindin and NeuN. Interestingly, folic acid reversed the expression of these critical pro-neurogenic mediators to mitigate these degenerative changes to promote neurogenesis. Delving deep, we found that folic acid rescued arsenic-exposed cerebellum from severe oxidative and pro-inflammatory insults by increasing antioxidants like SOD, Catalase, GSH, upregulating Nrf2 and downregulating M1 macrophages, JNK, NF-κB, and STAT3 activities. For the first time, we are reporting that arsenic induced a G1/S cell cycle arrest and triggered apoptosis in mouse cerebellum by activating the p53-p21 axis, downregulating CDKs and instigated p21-mediated suppression of SOX2 transcriptional activity. Folic acid abated such alterations by modulating the p53/p21/SOX2 axis. Collectively, the anti-apoptotic and pro-neurogenic effects of folic acid present it as a promising therapeutic candidate, warranting further research into its efficacy against metal-induced neurodegenerative disorders.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1007/s10495-024-02058-w
Xiaopei Yan, Li Xu, Chang Qi, Yiling Chang, Juanjuan Zhang, Ning Li, Baoyu Shi, Bo Guan, Siming Hu, Chao Huang, Hui Wang, Ying Chen, Xiao Xu, Jian Lu, Guopeng Xu, Chao Chen, Su Li, Yuqiong Chen
Ferroptosis is a novel type of programmed cell death dependent on iron and is characterized by the accumulation of lipid peroxides, which is involved in acute lung injury (ALI). Brazilin, an organic compound known for its potent antioxidant and anti-inflammatory properties, has not been thoroughly studied for its potential impact on lipopolysaccharide (LPS)-induced ALI. Here, we found that pretreatment of brazilin mitigated LPS-induced lung injury and inflammation by inhibiting mitochondrial oxidative stress and ferroptosis, both in vivo and in vitro. Sirtuin 3 (SIRT3) was identified as a downstream target of brazilin, and overexpression of SIRT3 mirrored the protective effects of brazilin against LPS-induced ALI. Additionally, SIRT3 contributed to the upregulation, mitochondrial translocation and deacetylation of glutathione peroxidase 4 (GPX4). Through screening potential acetylation sites on GPX4, we identified lysine 148 (K148) as the residue deacetylated by SIRT3. Mutating the acetylation site of GPX4 within mitochondria (mitoGPX4-K148R) reduced LPS or SIRT3 knockdown-induced GPX4 acetylation, oxidative stress, and ferroptosis, ultimately ameliorating ALI. In conclusion, our study demonstrates the beneficial effects of brazilin in treating LPS-induced ALI. Brazilin enhances SIRT3 expression, which in turn deacetylates and facilitates the mitochondrial translocation of GPX4, thereby reducing mitochondrial oxidative stress and ferroptosis. These findings suggest that the SIRT3/GPX4 pathway may represent a critical mechanism, and brazilin emerges as a promising therapeutic candidate for ALI.
{"title":"Brazilin alleviates acute lung injury via inhibition of ferroptosis through the SIRT3/GPX4 pathway.","authors":"Xiaopei Yan, Li Xu, Chang Qi, Yiling Chang, Juanjuan Zhang, Ning Li, Baoyu Shi, Bo Guan, Siming Hu, Chao Huang, Hui Wang, Ying Chen, Xiao Xu, Jian Lu, Guopeng Xu, Chao Chen, Su Li, Yuqiong Chen","doi":"10.1007/s10495-024-02058-w","DOIUrl":"https://doi.org/10.1007/s10495-024-02058-w","url":null,"abstract":"<p><p>Ferroptosis is a novel type of programmed cell death dependent on iron and is characterized by the accumulation of lipid peroxides, which is involved in acute lung injury (ALI). Brazilin, an organic compound known for its potent antioxidant and anti-inflammatory properties, has not been thoroughly studied for its potential impact on lipopolysaccharide (LPS)-induced ALI. Here, we found that pretreatment of brazilin mitigated LPS-induced lung injury and inflammation by inhibiting mitochondrial oxidative stress and ferroptosis, both in vivo and in vitro. Sirtuin 3 (SIRT3) was identified as a downstream target of brazilin, and overexpression of SIRT3 mirrored the protective effects of brazilin against LPS-induced ALI. Additionally, SIRT3 contributed to the upregulation, mitochondrial translocation and deacetylation of glutathione peroxidase 4 (GPX4). Through screening potential acetylation sites on GPX4, we identified lysine 148 (K148) as the residue deacetylated by SIRT3. Mutating the acetylation site of GPX4 within mitochondria (mitoGPX4-K148R) reduced LPS or SIRT3 knockdown-induced GPX4 acetylation, oxidative stress, and ferroptosis, ultimately ameliorating ALI. In conclusion, our study demonstrates the beneficial effects of brazilin in treating LPS-induced ALI. Brazilin enhances SIRT3 expression, which in turn deacetylates and facilitates the mitochondrial translocation of GPX4, thereby reducing mitochondrial oxidative stress and ferroptosis. These findings suggest that the SIRT3/GPX4 pathway may represent a critical mechanism, and brazilin emerges as a promising therapeutic candidate for ALI.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1007/s10495-024-02049-x
Mingrui Jiang, Sen Wang, Jin Ji, Shantanu Baral, Qiannan Sun, Yong Wang, Bin Liu, Jun Ren, Wei Wang, Daorong Wang
Gastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis often depends on early detection and understanding the molecular mechanisms involved in its progression. Periodic tryptophan protein 1 (PWP1) has emerged as a novel diagnostic marker, potentially linked to gastric cancer progression. This study aims to elucidate the impact of PWP1 on gastric cancer development, focusing on apoptosis, cell cycle regulation, and the role of p53. This study utilized gastric cancer cell lines to investigate the expression and functional role of Pwp1. Quantitative PCR and Western blot analyses were conducted to measure PWP1 expression levels. Apoptosis was assessed by using flow cytometry and TUNEL assays, and cell cycle analysis was performed to evaluate the impact of PWP1 modulation. Additionally, animal experiments were conducted using mouse models injected with gastric cancer cells, with PWP1 knockdown or overexpression, to observe tumor growth and progression. Statistical significance was evaluated using t-tests and ANOVA where appropriate. Elevated PWP1 expression was observed in gastric cancer tissues compared to normal tissues. PWP1's knockdown resulted in increased apoptosis and cell cycle arrest at the G1 phase, suggesting its role in promoting invasion and proliferation. Furthermore, animal experiments demonstrated reduced tumor growth in mice with PWP1 knockdown. PWP1 was found to transcriptionally regulate p53, affecting its expression and thereby influencing apoptosis and cell cycle pathways in gastric cancer. Our study identifies PWP1 as a novel oncogene frequently overexpressed in gastric cancer (GC). Through transcriptional regulation of p53, PWP1 enhances cell growth by influencing apoptosis and inducing G1 phase cell cycle arrest. These findings underscore PWP1 as a promising therapeutic target for treating GC, suggesting its potential for future clinical applications.
{"title":"PWP1 transcriptionally regulates p53, modulating apoptosis and cell cycle to promote gastric cancer progression.","authors":"Mingrui Jiang, Sen Wang, Jin Ji, Shantanu Baral, Qiannan Sun, Yong Wang, Bin Liu, Jun Ren, Wei Wang, Daorong Wang","doi":"10.1007/s10495-024-02049-x","DOIUrl":"https://doi.org/10.1007/s10495-024-02049-x","url":null,"abstract":"<p><p>Gastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis often depends on early detection and understanding the molecular mechanisms involved in its progression. Periodic tryptophan protein 1 (PWP1) has emerged as a novel diagnostic marker, potentially linked to gastric cancer progression. This study aims to elucidate the impact of PWP1 on gastric cancer development, focusing on apoptosis, cell cycle regulation, and the role of p53. This study utilized gastric cancer cell lines to investigate the expression and functional role of Pwp1. Quantitative PCR and Western blot analyses were conducted to measure PWP1 expression levels. Apoptosis was assessed by using flow cytometry and TUNEL assays, and cell cycle analysis was performed to evaluate the impact of PWP1 modulation. Additionally, animal experiments were conducted using mouse models injected with gastric cancer cells, with PWP1 knockdown or overexpression, to observe tumor growth and progression. Statistical significance was evaluated using t-tests and ANOVA where appropriate. Elevated PWP1 expression was observed in gastric cancer tissues compared to normal tissues. PWP1's knockdown resulted in increased apoptosis and cell cycle arrest at the G1 phase, suggesting its role in promoting invasion and proliferation. Furthermore, animal experiments demonstrated reduced tumor growth in mice with PWP1 knockdown. PWP1 was found to transcriptionally regulate p53, affecting its expression and thereby influencing apoptosis and cell cycle pathways in gastric cancer. Our study identifies PWP1 as a novel oncogene frequently overexpressed in gastric cancer (GC). Through transcriptional regulation of p53, PWP1 enhances cell growth by influencing apoptosis and inducing G1 phase cell cycle arrest. These findings underscore PWP1 as a promising therapeutic target for treating GC, suggesting its potential for future clinical applications.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1007/s10495-024-02064-y
Xiaochen Yan, Peng Jiang, Changqing Li, Fengjuan Liu, Ping Fu, Dengqun Liu, Xi Du, Li Ma, Tong Wang, Xin Yuan, Shengliang Ye, Zongkui Wang
Background: Chemotherapy-induced mucositis (CIM) significantly impacts quality of life and reduces survival in patients treated with specific chemotherapeutic agents. However, effective clinical treatments for CIM remain limited. Intravenous immunoglobulin (IVIg), a therapeutic derived from pooled human plasma, is widely used to treat inflammatory diseases. This study aimed to evaluate the therapeutic efficacy and underlying mechanisms of IVIg in CIM.
Methods: A murine model of doxorubicin (Dox)-induced intestinal mucositis and an organoid model of small intestinal injury were used to explore the protective effects of IVIg on CIM. Immunostaining, transmission electron microscopy (TEM), western blotting (WB), and proteomic analysis were used to further investigate ferroptosis in intestinal epithelial cells and the underlying mechanisms.
Results: In the murine model of Dox-induced intestinal mucositis, intestinal epithelial barrier was destroyed and ferroptosis increased, characterized by weight loss, hematological injury, inflammation, mitochondrial atrophy in intestinal epithelial cells, lipid peroxidation, impairment of tight junctions, and damage to intestinal microvilli. IVIg treatment significantly ameliorated intestinal epithelial barrier damage and reduced ferroptosis both in vitro and in vivo. Proteomic analysis revealed that the FcγR-mediated phagocytosis signaling pathway was involved in the therapeutic effects of IVIg on CIM mice. WB results demonstrated that key proteins downstream of this pathway, Syk, PI3K, and Akt, showed increased phosphorylation in CIM mice, whereas IVIg treatment significantly reduced the phosphorylation levels. Furthermore, the inhibitory effects of IVIg on Dox-induced activation of the Syk/PI3K/Akt axis and ferroptosis, as well as its protective effects on intestinal inflammation and intestinal barrier damage, were reversed by 740Y-P (an PI3K activator) or SC79 (an Akt activator).
Conclusions: Our findings highlight that IVIg ameliorates CIM by inhibiting ferroptosis via the Syk/PI3K/Akt axis. These results suggest that IVIg may represent a potential therapeutic approach for CIM.
{"title":"Intravenous immunoglobulin ameliorates doxorubicin-induced intestinal mucositis by inhibiting the Syk/PI3K/Akt axis and ferroptosis.","authors":"Xiaochen Yan, Peng Jiang, Changqing Li, Fengjuan Liu, Ping Fu, Dengqun Liu, Xi Du, Li Ma, Tong Wang, Xin Yuan, Shengliang Ye, Zongkui Wang","doi":"10.1007/s10495-024-02064-y","DOIUrl":"https://doi.org/10.1007/s10495-024-02064-y","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy-induced mucositis (CIM) significantly impacts quality of life and reduces survival in patients treated with specific chemotherapeutic agents. However, effective clinical treatments for CIM remain limited. Intravenous immunoglobulin (IVIg), a therapeutic derived from pooled human plasma, is widely used to treat inflammatory diseases. This study aimed to evaluate the therapeutic efficacy and underlying mechanisms of IVIg in CIM.</p><p><strong>Methods: </strong>A murine model of doxorubicin (Dox)-induced intestinal mucositis and an organoid model of small intestinal injury were used to explore the protective effects of IVIg on CIM. Immunostaining, transmission electron microscopy (TEM), western blotting (WB), and proteomic analysis were used to further investigate ferroptosis in intestinal epithelial cells and the underlying mechanisms.</p><p><strong>Results: </strong>In the murine model of Dox-induced intestinal mucositis, intestinal epithelial barrier was destroyed and ferroptosis increased, characterized by weight loss, hematological injury, inflammation, mitochondrial atrophy in intestinal epithelial cells, lipid peroxidation, impairment of tight junctions, and damage to intestinal microvilli. IVIg treatment significantly ameliorated intestinal epithelial barrier damage and reduced ferroptosis both in vitro and in vivo. Proteomic analysis revealed that the FcγR-mediated phagocytosis signaling pathway was involved in the therapeutic effects of IVIg on CIM mice. WB results demonstrated that key proteins downstream of this pathway, Syk, PI3K, and Akt, showed increased phosphorylation in CIM mice, whereas IVIg treatment significantly reduced the phosphorylation levels. Furthermore, the inhibitory effects of IVIg on Dox-induced activation of the Syk/PI3K/Akt axis and ferroptosis, as well as its protective effects on intestinal inflammation and intestinal barrier damage, were reversed by 740Y-P (an PI3K activator) or SC79 (an Akt activator).</p><p><strong>Conclusions: </strong>Our findings highlight that IVIg ameliorates CIM by inhibiting ferroptosis via the Syk/PI3K/Akt axis. These results suggest that IVIg may represent a potential therapeutic approach for CIM.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1007/s10495-024-02060-2
Shanshan Wei, Wei Xia, Jun Feng, Jianwen Lu, Luo Zhang, Wei Wang, Wenwei Hu, Yiting Geng
5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents for colorectal cancer (CRC), but its application is often limited by resistance. Tripartite motif containing 23 (TRIM23) has been reported to be dysregulated in various tumors and involved in tumor progression and chemotherapy resistance. However, its relationship with CRC 5-FU resistance and the underlying mechanism are still unclear. In this study, we found that TRIM23 was upregulated in CRC. Patients treated with 5-FU and with high TRIM23 expression had a lower disease control rate (DCR) and a poorer median progression-free survival (mPFS). In vitro, the expression of TRIM23 in CRC cells was elevated after 5-FU treatment. Compared to parental cells, TRIM23 was significantly overexpressed in 5-FU-resistant CRC cells. Mechanistically, TRIM23 mediated 5-FU resistance of CRC by upregulating the expression of N-acetylgalactosaminyltransferase-4 (GALNT4). Knocking down TRIM23 in 5-FU-resistant colon cancer cells restored the sensitivity to 5-FU, while overexpression of GALNT4 in TRIM23 knockdown cells counteracted the chemosensitization caused by TRIM23 downregulation. The TRIM23/GALNT4 axis may play a crucial role in 5-FU resistance in CRC, and targeted inhibition of this axis is expected to reverse resistance. As a potential biomarker for screening 5-FU-sensitive patients and predicting prognosis in clinical practice, TRIM23 deserves further investigation.
{"title":"TRIM23 promotes 5-Fluorouracil resistance in colorectal cancer by upregulating GALNT4 expression.","authors":"Shanshan Wei, Wei Xia, Jun Feng, Jianwen Lu, Luo Zhang, Wei Wang, Wenwei Hu, Yiting Geng","doi":"10.1007/s10495-024-02060-2","DOIUrl":"https://doi.org/10.1007/s10495-024-02060-2","url":null,"abstract":"<p><p>5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents for colorectal cancer (CRC), but its application is often limited by resistance. Tripartite motif containing 23 (TRIM23) has been reported to be dysregulated in various tumors and involved in tumor progression and chemotherapy resistance. However, its relationship with CRC 5-FU resistance and the underlying mechanism are still unclear. In this study, we found that TRIM23 was upregulated in CRC. Patients treated with 5-FU and with high TRIM23 expression had a lower disease control rate (DCR) and a poorer median progression-free survival (mPFS). In vitro, the expression of TRIM23 in CRC cells was elevated after 5-FU treatment. Compared to parental cells, TRIM23 was significantly overexpressed in 5-FU-resistant CRC cells. Mechanistically, TRIM23 mediated 5-FU resistance of CRC by upregulating the expression of N-acetylgalactosaminyltransferase-4 (GALNT4). Knocking down TRIM23 in 5-FU-resistant colon cancer cells restored the sensitivity to 5-FU, while overexpression of GALNT4 in TRIM23 knockdown cells counteracted the chemosensitization caused by TRIM23 downregulation. The TRIM23/GALNT4 axis may play a crucial role in 5-FU resistance in CRC, and targeted inhibition of this axis is expected to reverse resistance. As a potential biomarker for screening 5-FU-sensitive patients and predicting prognosis in clinical practice, TRIM23 deserves further investigation.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Copper (cu) is an essential micronutrient required for numerous metabolic processes. It plays a crucial role in cellular respiration by participating in the electron transport chain and facilitating numerous biological reactions. Various diseases, including cancer, demonstrate localized elevation of copper levels and/or alterations in the overall distribution of copper. Modulating local or systemic copper levels as a novel therapeutic approach for treating and ameliorating diseases has emerged as a prominent trend in disease management, particularly in the realm of cancer therapy, which is currently under investigation. The objective of this review is to offer a thorough examination of copper metabolism in both physiological and pathological contexts. Specifically, it delves into how copper ions can effectively target and stimulate tumor cell death via the process known as cuproptosis in cancer patients. Furthermore, this review explores the utilization of three categories of anticancer medications (copper ion carriers, copper complexes, and copper chelating agents) pertaining to copper metabolism within the realm of cancer therapy, elucidating on the distinct mechanisms through which they exert their effects.
{"title":"Involvement of copper in cell death and cancer.","authors":"Jiahao Xie, Yue Su, Wenzhong Shang, Yanfang Wu, Junjia He, Ting Li, Yeyu Shen, Youni Zhang, Xiangmin Tong, Qiong Bian","doi":"10.1007/s10495-024-02059-9","DOIUrl":"https://doi.org/10.1007/s10495-024-02059-9","url":null,"abstract":"<p><p>Copper (cu) is an essential micronutrient required for numerous metabolic processes. It plays a crucial role in cellular respiration by participating in the electron transport chain and facilitating numerous biological reactions. Various diseases, including cancer, demonstrate localized elevation of copper levels and/or alterations in the overall distribution of copper. Modulating local or systemic copper levels as a novel therapeutic approach for treating and ameliorating diseases has emerged as a prominent trend in disease management, particularly in the realm of cancer therapy, which is currently under investigation. The objective of this review is to offer a thorough examination of copper metabolism in both physiological and pathological contexts. Specifically, it delves into how copper ions can effectively target and stimulate tumor cell death via the process known as cuproptosis in cancer patients. Furthermore, this review explores the utilization of three categories of anticancer medications (copper ion carriers, copper complexes, and copper chelating agents) pertaining to copper metabolism within the realm of cancer therapy, elucidating on the distinct mechanisms through which they exert their effects.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}