Pub Date : 2024-09-30DOI: 10.1016/j.bbamcr.2024.119852
Keying Mi , Xiaoyan Wang , Chao Ma , Yinghua Tan , Gang Zhao , Xinran Cao , Haitao Yuan
Endoplasmic reticulum stress-induced cell apoptosis is a pivotal mechanism underlying the progression of cardiac hypertrophy. NLRX1, a member of the NOD-like receptor family, modulates various cellular processes, including STING, NF-κB, MAPK pathways, reactive oxygen species production, essential metabolic pathways, autophagy and cell death. Emerging evidence suggests that NLRX1 may offer protection against diverse cardiac diseases. However, the impacts and mechanisms of NLRX1 on endoplasmic reticulum stress in cardiac hypertrophy remains largely unexplored. In our study, we observed that the NLRX1 and phosphorylated STING (p-STING) were highly expressed in both hypertrophic mouse heart and cellular model of cardiac hypertrophy. Whereas over-expression of NLRX1 mitigated the expression levels of p-STING, as well as the endoplasmic reticulum stress markers, including transcription activating factor 4 (ATF4), C/EBP homologous protein (CHOP) and the ratios of phosphorylated PERK to PERK, phosphorylated IRE1 to IRE1 and phosphorylated eIF2α to eIF2α in an Angiotensin II (Ang II)-induced cellular model of cardiac hypertrophy. Importantly, the protective effects of NLRX1 were attenuated upon pretreatment with the STING agonist, DMXAA. Our findings provide the evidence that NLRX1 attenuates the PERK-eIF2α-ATF4-CHOP axis of endoplasmic reticulum stress response via inhibition of p-STING in Ang II-treated cardiomyocytes, thereby ameliorating the development of cardiac hypertrophy.
{"title":"NLRX1 attenuates endoplasmic reticulum stress via STING in cardiac hypertrophy","authors":"Keying Mi , Xiaoyan Wang , Chao Ma , Yinghua Tan , Gang Zhao , Xinran Cao , Haitao Yuan","doi":"10.1016/j.bbamcr.2024.119852","DOIUrl":"10.1016/j.bbamcr.2024.119852","url":null,"abstract":"<div><div>Endoplasmic reticulum stress-induced cell apoptosis is a pivotal mechanism underlying the progression of cardiac hypertrophy. NLRX1, a member of the NOD-like receptor family, modulates various cellular processes, including STING, NF-κB, MAPK pathways, reactive oxygen species production, essential metabolic pathways, autophagy and cell death. Emerging evidence suggests that NLRX1 may offer protection against diverse cardiac diseases. However, the impacts and mechanisms of NLRX1 on endoplasmic reticulum stress in cardiac hypertrophy remains largely unexplored. In our study, we observed that the NLRX1 and phosphorylated STING (p-STING) were highly expressed in both hypertrophic mouse heart and cellular model of cardiac hypertrophy. Whereas over-expression of NLRX1 mitigated the expression levels of p-STING, as well as the endoplasmic reticulum stress markers, including transcription activating factor 4 (ATF4), C/EBP homologous protein (CHOP) and the ratios of phosphorylated PERK to PERK, phosphorylated IRE1 to IRE1 and phosphorylated eIF2α to eIF2α in an Angiotensin II (Ang II)-induced cellular model of cardiac hypertrophy. Importantly, the protective effects of NLRX1 were attenuated upon pretreatment with the STING agonist, DMXAA. Our findings provide the evidence that NLRX1 attenuates the PERK-eIF2α-ATF4-CHOP axis of endoplasmic reticulum stress response via inhibition of p-STING in Ang II-treated cardiomyocytes, thereby ameliorating the development of cardiac hypertrophy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119852"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.bbamcr.2024.119854
Philip Salu , Daniel Tuvin , Katie M. Reindl
Anterior gradient 2 (AGR2) is often overexpressed in many human cancers, including pancreatic ductal adenocarcinoma (PDAC). Elevated AGR2 expression is known to play a critical role in tumor development, progression, and metastasis and positively correlates with poor patient survival. However, the relationship between AGR2 expression and tumor growth is not fully understood. Our study aims to investigate the impact of AGR2 knockdown on the survival of two pancreatic cancer cell lines, HPAF–II and PANC–1, that exhibit high AGR2 expression. This study revealed that the knockdown of AGR2 expression through an inducible shRNA-mediated approach reduced the proliferative ability and colony-forming potential of PDAC cells compared to scramble controls. Significantly, knocking down AGR2 led to the inhibition of multiple protein biosynthesis pathways and induced ER stress through unfolded protein response (UPR) activation. AGR2 knockdown induced ER stress and increased mitochondrial fission, while mitochondrial fusion remained unaffected. Ultimately, apoptotic cell death was heightened in AGR2 knockdown PDAC cells compared to the controls. Overall, these data reveal a new axis involving AGR2-ER stress-associated mitochondrial fission that could be targeted to improve PDAC patient outcomes.
{"title":"AGR2 knockdown induces ER stress and mitochondria fission to facilitate pancreatic cancer cell death","authors":"Philip Salu , Daniel Tuvin , Katie M. Reindl","doi":"10.1016/j.bbamcr.2024.119854","DOIUrl":"10.1016/j.bbamcr.2024.119854","url":null,"abstract":"<div><div>Anterior gradient 2 (AGR2) is often overexpressed in many human cancers, including pancreatic ductal adenocarcinoma (PDAC). Elevated AGR2 expression is known to play a critical role in tumor development, progression, and metastasis and positively correlates with poor patient survival. However, the relationship between AGR2 expression and tumor growth is not fully understood. Our study aims to investigate the impact of AGR2 knockdown on the survival of two pancreatic cancer cell lines, HPAF–II and PANC–1, that exhibit high AGR2 expression. This study revealed that the knockdown of AGR2 expression through an inducible shRNA-mediated approach reduced the proliferative ability and colony-forming potential of PDAC cells compared to scramble controls. Significantly, knocking down AGR2 led to the inhibition of multiple protein biosynthesis pathways and induced ER stress through unfolded protein response (UPR) activation. AGR2 knockdown induced ER stress and increased mitochondrial fission, while mitochondrial fusion remained unaffected. Ultimately, apoptotic cell death was heightened in AGR2 knockdown PDAC cells compared to the controls. Overall, these data reveal a new axis involving AGR2-ER stress-associated mitochondrial fission that could be targeted to improve PDAC patient outcomes.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119854"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364198","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 : 2024-09-30DOI: 10.1016/j.bbamcr.2024.119853
Yumeng Yang , Yanan Li , Hanxiao Shang , Yueyang Liu , Wenying Li , Limin Chen , Na Cheng , Yuchen Zhang , Nan Zhang , Yanxia Yin , Li Tong , Zhimei Li , Jingyu Yang , Jing Luo
We previously reported that a bioactive peptide (pep3) can potently inhibit the enzyme activity of purified calcineurin (CN). In this paper, we further demonstrate that transfected pep3 can strongly inhibit CN enzyme activity in HEK293 cells. Transcription factor EB (TFEB) plays an important role in the autophagy-lysosome pathway (ALP) as one of the substrates of CN, so we study the effect of pep3 on the CN-TFEB-ALP pathway. Pep3 can significantly inhibit the mRNA levels of the TFEB downstream genes and the expression of the autophagy-associated proteins, and autophagy flux in HEK293 cells. We also validated the inhibitory effect of pep3 on autophagy in mice. These findings may provide a new idea for discovering more CN inhibitors and autophagy inhibitory drugs.
{"title":"An artificial peptide inhibits autophagy through calcineurin-TFEB pathway","authors":"Yumeng Yang , Yanan Li , Hanxiao Shang , Yueyang Liu , Wenying Li , Limin Chen , Na Cheng , Yuchen Zhang , Nan Zhang , Yanxia Yin , Li Tong , Zhimei Li , Jingyu Yang , Jing Luo","doi":"10.1016/j.bbamcr.2024.119853","DOIUrl":"10.1016/j.bbamcr.2024.119853","url":null,"abstract":"<div><div>We previously reported that a bioactive peptide (pep3) can potently inhibit the enzyme activity of purified calcineurin (CN). In this paper, we further demonstrate that transfected pep3 can strongly inhibit CN enzyme activity in HEK293 cells. Transcription factor EB (TFEB) plays an important role in the autophagy-lysosome pathway (ALP) as one of the substrates of CN, so we study the effect of pep3 on the CN-TFEB-ALP pathway. Pep3 can significantly inhibit the mRNA levels of the TFEB downstream genes and the expression of the autophagy-associated proteins, and autophagy flux in HEK293 cells. We also validated the inhibitory effect of pep3 on autophagy in mice. These findings may provide a new idea for discovering more CN inhibitors and autophagy inhibitory drugs.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119853"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364199","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 : 2024-09-30DOI: 10.1016/j.bbamcr.2024.119855
Fangyu Hu , Lingling Zhao , Junyu Wang , Xiaoying Li , Zixuan Xue , Yimeng Ma , Minghui Zheng , Chenglin Chen , Meiting Tong , Xiaohuan Guo , Hongyan Li , Honglei Jin , Qipeng Xie , Xiaodong Zhang , Chuanshu Huang , Haishan Huang
Background
Colorectal cancer (CRC) is the most common malignancy of the digestive tract, and to date, morbidity and mortality rates remain high. While existing therapeutic methods have achieved certain effective outcomes, there are still many problems in treating this disease. Therefore, it is still urgent to constantly find new therapeutic targets in CRC that could lead to new therapeutics.
Methods
Immunohistochemistry, Real-time PCR and Western Blot were employed to measure mRNA and protein levels of the target protein, respectively. The proliferation ability of CRC cells was evaluated using ATP assay, Soft agar assay, and nude mouse subcutaneous tumorigenesis assay. Protein Degradation Assay was conducted to determine protein degradation rate, while Ubiquitination assay was used to assess the ubiquitination modification level of target proteins. Immunoprecipitation assay was used to study protein interactions, and pull-down assay was employed to investigate direct interactions between proteins.
Results
TRIM40 was significantly down-regulated in CRC tissues, with its expression levels positively correlating with disease prognosis. Using both in vitro and in vivo approaches, it was demonstrated that TRIM40 could significantly inhibit the proliferation of CRC cells. Molecular mechanism studies showed that TRIM40 directly binds to and ubiquitinates ROCK1 protein, accelerating its degradation and subsequently reducing the stability of c-Myc protein. This cascade of events results in the release of transcriptional inhibition of p21 by c-Myc, leading to increased p21 expression and G0/G1 phase arrest in CRC cells.
Conclusion
This research suggests that TRIM40 could be a valuable therapeutic target for the treatment of CRC.
{"title":"TRIM40 interacts with ROCK1 directly and inhibits colorectal cancer cell proliferation through the c-Myc/p21 axis","authors":"Fangyu Hu , Lingling Zhao , Junyu Wang , Xiaoying Li , Zixuan Xue , Yimeng Ma , Minghui Zheng , Chenglin Chen , Meiting Tong , Xiaohuan Guo , Hongyan Li , Honglei Jin , Qipeng Xie , Xiaodong Zhang , Chuanshu Huang , Haishan Huang","doi":"10.1016/j.bbamcr.2024.119855","DOIUrl":"10.1016/j.bbamcr.2024.119855","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer (CRC) is the most common malignancy of the digestive tract, and to date, morbidity and mortality rates remain high. While existing therapeutic methods have achieved certain effective outcomes, there are still many problems in treating this disease. Therefore, it is still urgent to constantly find new therapeutic targets in CRC that could lead to new therapeutics.</div></div><div><h3>Methods</h3><div>Immunohistochemistry, Real-time PCR and Western Blot were employed to measure mRNA and protein levels of the target protein, respectively. The proliferation ability of CRC cells was evaluated using ATP assay, Soft agar assay, and nude mouse subcutaneous tumorigenesis assay. Protein Degradation Assay was conducted to determine protein degradation rate, while Ubiquitination assay was used to assess the ubiquitination modification level of target proteins. Immunoprecipitation assay was used to study protein interactions, and pull-down assay was employed to investigate direct interactions between proteins.</div></div><div><h3>Results</h3><div>TRIM40 was significantly down-regulated in CRC tissues, with its expression levels positively correlating with disease prognosis. Using both <em>in vitro</em> and <em>in vivo</em> approaches, it was demonstrated that TRIM40 could significantly inhibit the proliferation of CRC cells. Molecular mechanism studies showed that TRIM40 directly binds to and ubiquitinates ROCK1 protein, accelerating its degradation and subsequently reducing the stability of c-Myc protein. This cascade of events results in the release of transcriptional inhibition of p21 by c-Myc, leading to increased p21 expression and G0/G1 phase arrest in CRC cells.</div></div><div><h3>Conclusion</h3><div>This research suggests that TRIM40 could be a valuable therapeutic target for the treatment of CRC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119855"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364211","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 : 2024-09-25DOI: 10.1016/j.bbamcr.2024.119851
M. Zamorano-Cataldo , I. Vega-Vásquez , C. García-Navarrete , J. Toledo , D. Bustamante , F. Ezquer , F.A. Urra , N. Farfán-Troncoso , M. Herrera-Marschitz , P. Morales
Aims
Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects.
Materials and methods
Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨm) (Safranin O) were evaluated at P1 and P7 in the hippocampus.
Key findings
Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨm at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission.
Significance
This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.
{"title":"Mitochondrial dynamics and sex-specific responses in the developing rat hippocampus: Effect of perinatal asphyxia and mesenchymal stem cell Secretome treatment","authors":"M. Zamorano-Cataldo , I. Vega-Vásquez , C. García-Navarrete , J. Toledo , D. Bustamante , F. Ezquer , F.A. Urra , N. Farfán-Troncoso , M. Herrera-Marschitz , P. Morales","doi":"10.1016/j.bbamcr.2024.119851","DOIUrl":"10.1016/j.bbamcr.2024.119851","url":null,"abstract":"<div><h3>Aims</h3><div>Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects.</div></div><div><h3>Materials and methods</h3><div>Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨ<sub>m</sub>) (Safranin O) were evaluated at P1 and P7 in the hippocampus.</div></div><div><h3>Key findings</h3><div>Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨ<sub>m</sub> at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission.</div></div><div><h3>Significance</h3><div>This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119851"},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340299","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 : 2024-09-19DOI: 10.1016/j.bbamcr.2024.119850
Joo-Young Cho , Hee-Eun Woo , Jiah Yeom , Mirae An , Seongho Ma , Dong Joon Yim , Sang-Hun Kim , Young-Hee Lim
Osteoclasts play a crucial role in bone destruction in rheumatoid arthritis (RA). This study aimed to investigate the inhibitory effects of chaperonin 60 (CPN60), identified in the surface proteins of Propionibacterium freudenreichii MJ2, on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation, and elucidate the underlying mechanisms. Treatment with CPN60 inhibited RANKL-induced osteoclast differentiation by decreasing the expression of osteoclast differentiation-related genes and proteins. CPN60 interfered with the binding of RANKL to RANK, as elucidated using surface plasmon resonance (SPR) and immunofluorescence. In silico molecular docking analysis further supported the interference of CPN60 with the binding of RANKL and RANK. CPN60 suppressed the expression of molecules linked to the calcium-dependent pathway in RANKL-induced osteoclast differentiation at both mRNA and protein levels. Microarray analysis showed elevated expression of lipocalin 2 (Lcn2), which was closely linked to the inhibition of osteoclast differentiation in CPN60-treated RAW 264.7 cells. Inhibition of Lcn2 decreased the inhibitory effect of CPN60 on osteoclast differentiation, indicating that increased expression of Lcn2 by CPN60 contributes to the inhibition of osteoclastogenesis. In addition, CPN60 treatment alleviated arthritis symptoms in collagen-induced arthritis mice by reducing the generation of collagen-specific antibodies and inhibiting osteoclast differentiation. In conclusion, CPN60 of P. freudenreichii MJ2 interfered with RANKL–RANK binding, reduced the expression of genes and proteins related to osteoclast differentiation and upregulated Lcn2 expression, thereby inhibiting RANKL-induced osteoclast differentiation, which might contribute to ameliorate collagen-induced arthritis.
{"title":"Microbial chaperonin 60 inhibits osteoclast differentiation by interfering with RANK/RANKL binding and overexpression of lipocalin2","authors":"Joo-Young Cho , Hee-Eun Woo , Jiah Yeom , Mirae An , Seongho Ma , Dong Joon Yim , Sang-Hun Kim , Young-Hee Lim","doi":"10.1016/j.bbamcr.2024.119850","DOIUrl":"10.1016/j.bbamcr.2024.119850","url":null,"abstract":"<div><div>Osteoclasts play a crucial role in bone destruction in rheumatoid arthritis (RA). This study aimed to investigate the inhibitory effects of chaperonin 60 (CPN60), identified in the surface proteins of <em>Propionibacterium freudenreichii</em> MJ2, on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation, and elucidate the underlying mechanisms. Treatment with CPN60 inhibited RANKL-induced osteoclast differentiation by decreasing the expression of osteoclast differentiation-related genes and proteins. CPN60 interfered with the binding of RANKL to RANK, as elucidated using surface plasmon resonance (SPR) and immunofluorescence. In silico molecular docking analysis further supported the interference of CPN60 with the binding of RANKL and RANK. CPN60 suppressed the expression of molecules linked to the calcium-dependent pathway in RANKL-induced osteoclast differentiation at both mRNA and protein levels. Microarray analysis showed elevated expression of lipocalin 2 (<em>Lcn2</em>), which was closely linked to the inhibition of osteoclast differentiation in CPN60-treated RAW 264.7 cells. Inhibition of <em>Lcn2</em> decreased the inhibitory effect of CPN60 on osteoclast differentiation, indicating that increased expression of <em>Lcn2</em> by CPN60 contributes to the inhibition of osteoclastogenesis. In addition, CPN60 treatment alleviated arthritis symptoms in collagen-induced arthritis mice by reducing the generation of collagen-specific antibodies and inhibiting osteoclast differentiation. In conclusion, CPN60 of <em>P. freudenreichii</em> MJ2 interfered with RANKL–RANK binding, reduced the expression of genes and proteins related to osteoclast differentiation and upregulated <em>Lcn2</em> expression, thereby inhibiting RANKL-induced osteoclast differentiation, which might contribute to ameliorate collagen-induced arthritis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119850"},"PeriodicalIF":4.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0167488924001939/pdfft?md5=d4dd96dafd55b9da3e8f86b0d4a71b9e&pid=1-s2.0-S0167488924001939-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.bbamcr.2024.119848
Anoy Kumar Das, Subhas C. Biswas
Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.
{"title":"Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRb/E2F1 pathway in a model of Parkinson's disease","authors":"Anoy Kumar Das, Subhas C. Biswas","doi":"10.1016/j.bbamcr.2024.119848","DOIUrl":"10.1016/j.bbamcr.2024.119848","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119848"},"PeriodicalIF":4.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279965","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 : 2024-09-19DOI: 10.1016/j.bbamcr.2024.119849
Keying Guo, Jie Zhou
The protein synthesis within eukaryotic cells is a complex process involving various translation factors. Among these factors, eukaryotic translation initiation factor 5 A (eIF5A) emerges as a crucial translation factor with high evolutionary conservation. eIF5A is unique as it is the only protein in eukaryotic cells containing the hypusine modification. Initially presumed to be a translation initiation factor, eIF5A was subsequently discovered to act mainly during the translation elongation phase. Notably, eIF5A facilitates the translation of peptide sequences containing polyproline stretches and exerts a universal regulatory effect on the elongation and termination phases of protein synthesis. Additionally, eIF5A indirectly affects various physiological processes within the cell by modulating the translation of specific proteins. This review provides a comprehensive overview of the structure, physiological functions, various post-translational modifications of eIF5A, and its association with various human diseases. The comparison between eIF5A and its bacterial homolog, EF-P, extends the discussion to the evolutionary conservation of eIF5A. This highlights its significance across different domains of life.
{"title":"Insights into eukaryotic translation initiation factor 5A: Its role and mechanisms in protein synthesis","authors":"Keying Guo, Jie Zhou","doi":"10.1016/j.bbamcr.2024.119849","DOIUrl":"10.1016/j.bbamcr.2024.119849","url":null,"abstract":"<div><div>The protein synthesis within eukaryotic cells is a complex process involving various translation factors. Among these factors, eukaryotic translation initiation factor 5 A (eIF5A) emerges as a crucial translation factor with high evolutionary conservation. eIF5A is unique as it is the only protein in eukaryotic cells containing the hypusine modification. Initially presumed to be a translation initiation factor, eIF5A was subsequently discovered to act mainly during the translation elongation phase. Notably, eIF5A facilitates the translation of peptide sequences containing polyproline stretches and exerts a universal regulatory effect on the elongation and termination phases of protein synthesis. Additionally, eIF5A indirectly affects various physiological processes within the cell by modulating the translation of specific proteins. This review provides a comprehensive overview of the structure, physiological functions, various post-translational modifications of eIF5A, and its association with various human diseases. The comparison between eIF5A and its bacterial homolog, EF-P, extends the discussion to the evolutionary conservation of eIF5A. This highlights its significance across different domains of life.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119849"},"PeriodicalIF":4.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1016/j.bbamcr.2024.119847
Jiaqi Zhu , Lijuan Mo , Mengying Li , Yunlei Wang , Gengming Zhang , Zhendong Tao , Xiaozhu Liao , Mingyuan Du , Hong He
The proliferation and mineralization of preosteoblasts is crucial for bone formation and has attracted extensive attentions for decades. However, the roles of numerous long non-coding RNAs (lncRNAs) in preosteoblasts have not been fully determined. This study aimed to investigate the function of lncRNA Snhg15 in preosteoblasts as well as the potential underlying mechanism. LncRNA Snhg15 was dynamically expressed during preosteoblast proliferation and mineralization, and its transcripts were localized mainly in the cytoplasm. LncRNA Snhg15 knockdown significantly inhibited the proliferation and mineralization of preosteoblasts in both a cellular model and a murine ectopic bone formation model. RNA-seq showed that lncRNA Snhg15 knockdown downregulated multiple proliferation-related genes, and cell cycle deregulation was verified by flow cytometry. Mechanistically, we found that lncRNA Snhg15 could bind to nucleolin (NCL), thereby block NCL ubiquitination and decrease its degradation. Furthermore, the overexpression of NCL in lncRNA Snhg15-knockdown preosteoblasts ameliorated GO/G1 phase cell cycle arrest. Moreover, experiments in an in situ bone formation model confirmed the negative effects of lncRNA Snhg15 deficiency on bone formation. In conclusion, this study revealed an important regulatory role of lncRNA Snhg15/NCL complex in preosteoblast proliferation and may provide insights into the molecular mechanisms underlying bone formation.
{"title":"Long non-coding RNA Snhg15 promotes preosteoblast proliferation by interacting with and stabilizing nucleolin","authors":"Jiaqi Zhu , Lijuan Mo , Mengying Li , Yunlei Wang , Gengming Zhang , Zhendong Tao , Xiaozhu Liao , Mingyuan Du , Hong He","doi":"10.1016/j.bbamcr.2024.119847","DOIUrl":"10.1016/j.bbamcr.2024.119847","url":null,"abstract":"<div><p>The proliferation and mineralization of preosteoblasts is crucial for bone formation and has attracted extensive attentions for decades. However, the roles of numerous long non-coding RNAs (lncRNAs) in preosteoblasts have not been fully determined. This study aimed to investigate the function of lncRNA <em>Snhg15</em> in preosteoblasts as well as the potential underlying mechanism. LncRNA <em>Snhg15</em> was dynamically expressed during preosteoblast proliferation and mineralization, and its transcripts were localized mainly in the cytoplasm. LncRNA <em>Snhg15</em> knockdown significantly inhibited the proliferation and mineralization of preosteoblasts in both a cellular model and a murine ectopic bone formation model. RNA-seq showed that lncRNA <em>Snhg15</em> knockdown downregulated multiple proliferation-related genes, and cell cycle deregulation was verified by flow cytometry. Mechanistically, we found that lncRNA <em>Snhg15</em> could bind to nucleolin (NCL), thereby block NCL ubiquitination and decrease its degradation. Furthermore, the overexpression of NCL in lncRNA <em>Snhg15</em>-knockdown preosteoblasts ameliorated GO/G1 phase cell cycle arrest. Moreover, experiments in an in situ bone formation model confirmed the negative effects of lncRNA <em>Snhg15</em> deficiency on bone formation. In conclusion, this study revealed an important regulatory role of lncRNA <em>Snhg15</em>/NCL complex in preosteoblast proliferation and may provide insights into the molecular mechanisms underlying bone formation.</p></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119847"},"PeriodicalIF":4.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239738","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 : 2024-09-14DOI: 10.1016/j.bbamcr.2024.119846
Huiwen Liu , Xiang Li , Wenbin Liu , Chunhong Zhang , Shuzhao Zhang , Xinran Zhou , Ann M. Bode , Xiangjian Luo
Background
Deregulation of lipid metabolism is one of the most prominent metabolic features in cancer. The activation of sphingolipid metabolic pathways affects the proliferation, invasion, angiogenesis, chemoresistance, and immune escape of tumors, including colorectal cancer (CRC). Dehydrogenase/reductase member 2 (DHRS2), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been reported to participate in the regulation of lipid metabolism and impact on cancer progression.
Trichothecin (TCN) is a sesquiterpenoid metabolite originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Studies have shown that TCN exerts a broad-spectrum antitumor activity.
Methods
We evaluated the proliferative ability of CRC cells by CCK8 and colony formation assays. A metabolite profiling using liquid chromatography coupled with mass spectrometry (LC/MS) was adopted to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA stability assay and RNA immunoprecipitation (RIP) experiments were applied to determine the post-transcriptional regulation of SPHK1 expression by DHRS2. We used flow cytometry to detect changes in cell cycle and cell apoptosis of CRC cells in the absence or presence of TCN.
Results
We demonstrate that DHRS2 hampers the sphingosine kinases 1 (SPHK1)/sphingosine 1-phosphate (S1P) metabolic pathway to inhibit CRC cell growth. DHRS2 directly binds to SPHK1 mRNA to accelerate its degradation in a post-transcriptionally regulatory manner. Moreover, we illustrate that SPHK1 downregulation induced by DHRS2 contributes to TCN-induced growth inhibition of CRC.
Conclusions
The present study provides a mechanistic connection among metabolic enzymes, metabolites, and the malignant progression of CRC. Moreover, TCN could be developed as a potential pharmacological tool against CRC by the induction of DHRS2 and targeting SPHK1/S1P metabolic pathway.
{"title":"DHRS2-induced SPHK1 downregulation contributes to the cell growth inhibition by Trichothecin in colorectal carcinoma","authors":"Huiwen Liu , Xiang Li , Wenbin Liu , Chunhong Zhang , Shuzhao Zhang , Xinran Zhou , Ann M. Bode , Xiangjian Luo","doi":"10.1016/j.bbamcr.2024.119846","DOIUrl":"10.1016/j.bbamcr.2024.119846","url":null,"abstract":"<div><h3>Background</h3><div>Deregulation of lipid metabolism is one of the most prominent metabolic features in cancer. The activation of sphingolipid metabolic pathways affects the proliferation, invasion, angiogenesis, chemoresistance, and immune escape of tumors, including colorectal cancer (CRC). Dehydrogenase/reductase member 2 (DHRS2), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been reported to participate in the regulation of lipid metabolism and impact on cancer progression.</div><div>Trichothecin (TCN) is a sesquiterpenoid metabolite originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Studies have shown that TCN exerts a broad-spectrum antitumor activity.</div></div><div><h3>Methods</h3><div>We evaluated the proliferative ability of CRC cells by CCK8 and colony formation assays. A metabolite profiling using liquid chromatography coupled with mass spectrometry (LC/MS) was adopted to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA stability assay and RNA immunoprecipitation (RIP) experiments were applied to determine the post-transcriptional regulation of <em>SPHK1</em> expression by DHRS2. We used flow cytometry to detect changes in cell cycle and cell apoptosis of CRC cells in the absence or presence of TCN.</div></div><div><h3>Results</h3><div>We demonstrate that DHRS2 hampers the sphingosine kinases 1 (SPHK1)/sphingosine 1-phosphate (S1P) metabolic pathway to inhibit CRC cell growth. DHRS2 directly binds to <em>SPHK1</em> mRNA to accelerate its degradation in a post-transcriptionally regulatory manner. Moreover, we illustrate that SPHK1 downregulation induced by DHRS2 contributes to TCN-induced growth inhibition of CRC.</div></div><div><h3>Conclusions</h3><div>The present study provides a mechanistic connection among metabolic enzymes, metabolites, and the malignant progression of CRC. Moreover, TCN could be developed as a potential pharmacological tool against CRC by the induction of DHRS2 and targeting SPHK1/S1P metabolic pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1871 8","pages":"Article 119846"},"PeriodicalIF":4.6,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279969","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}
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