1
|
Giroud J, Combémorel E, Pourtier A, Abbadie C, Pluquet O. Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response. Am J Physiol Cell Physiol 2025; 328:C1764-C1782. [PMID: 40257464 DOI: 10.1152/ajpcell.00091.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.
Collapse
Affiliation(s)
- Joëlle Giroud
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Emilie Combémorel
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Albin Pourtier
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Corinne Abbadie
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Olivier Pluquet
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| |
Collapse
|
2
|
Banuelos A, Baez M, Zhang A, Yılmaz L, Kasberg W, Volk R, Georgeos N, Koren-Sedova E, Le U, Burden AT, Marjon KD, Lippincott-Schwartz J, Zaro BW, Weissman IL. Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal. Proc Natl Acad Sci U S A 2025; 122:e2426644122. [PMID: 40397678 DOI: 10.1073/pnas.2426644122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 04/16/2025] [Indexed: 05/23/2025] Open
Abstract
Calreticulin (CALR) is primarily an endoplasmic reticulum chaperone protein that also plays a key role in facilitating programmed cell removal (PrCR) by acting as an "eat-me" signal for macrophages, directing their recognition and engulfment of dying, diseased, or unwanted cells. Recent findings have demonstrated that macrophages can transfer their own CALR onto exposed asialoglycans on target cells, marking them for PrCR. Despite the critical role CALR plays in this process, the molecular mechanisms behind its secretion by macrophages and the formation of binding sites on target cells remain unclear. Our findings show that CALR undergoes C-terminal cleavage upon secretion, producing a truncated form that functions as the active eat-me signal detectable on target cells. We identify cathepsins as potential proteases involved in this cleavage process. Furthermore, we demonstrate that macrophages release neuraminidases, which modify the surface of target cells and facilitate CALR binding. These insights reveal a coordinated mechanism through which lipopolysaccharide (LPS)-activated macrophages regulate CALR cleavage and neuraminidase activity to mark target cells for PrCR. How they recognize the cells to be targeted remains unknown.
Collapse
Affiliation(s)
- Allison Banuelos
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Michelle Baez
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Allison Zhang
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Leyla Yılmaz
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | | | - Regan Volk
- Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158
| | - Nardin Georgeos
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Elle Koren-Sedova
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Uyen Le
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Andrew T Burden
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Kristopher D Marjon
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | | | - Balyn W Zaro
- Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158
| | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305
- Department of Pathology, Stanford University, Stanford, CA 94305
| |
Collapse
|
3
|
Lee S. Effect of Tunicamycin on Viability, Motility, Reactive Oxygen Species, Nitric Oxide, and Lipid Peroxidation in Boar Sperm. Animals (Basel) 2025; 15:1422. [PMID: 40427299 PMCID: PMC12108351 DOI: 10.3390/ani15101422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/09/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Tunicamycin induces endoplasmic reticulum stress in mammalian cells. Our study aimed to investigate the effect of tunicamycin on the motility and viability of sperm, reactive oxygen species, nitric oxide, and lipid peroxidation in boar sperm. We treated 1.0, 2.0, 5.0, and 10 μM of tunicamycin in boar semen, and experimental treatments were performed. The viability (55.44%, 53.20, and 40.00%, p < 0.05) and motility (73.28%, 71.48%, and 54.48%, p < 0.05) of sperm at 2.0, 5.0, and 10.0 μM were decreased by tunicamycin, and the levels of reactive oxygen species and lipid peroxidation in tunicamycin-treated boar semen were increased (p < 0.05). However, the nitric oxide level was not changed by tunicamycin. Based on the results, we indicated that tunicamycin induces cell death by increasing oxidative stress in boar sperm, which may be the cause of decreased sperm viability and motility. Thus, we suggest that tunicamycin may induce cell death due to oxidative stress by reactive oxygen species and lipid peroxidation.
Collapse
Affiliation(s)
- Seunghyung Lee
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
| |
Collapse
|
4
|
Yang C, Huang L, Wang BC, Zhong Y, Ma X, Zhang C, Sun Q, Wu Y, Yao Y, Liu Q. Enhancing quality traits in staple crops: current advances and future perspectives. J Genet Genomics 2025:S1673-8527(25)00132-8. [PMID: 40348082 DOI: 10.1016/j.jgg.2025.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/30/2025] [Accepted: 05/03/2025] [Indexed: 05/14/2025]
Abstract
Staple crops such as rice, wheat and maize are crucial for global food security; however, improving their quality remains a significant challenge. This review summarizes recent advances in enhancing crop quality, focusing on key areas such as the molecular mechanisms underlying endosperm filling initiation, starch granule synthesis, protein body formation, and the interactions between carbon and nitrogen metabolism. It also highlights ten unresolved questions related to starch-protein spatial distribution, epigenetic regulation, and the environmental impacts on quality traits. The integration of multi-omics approaches, and rational design strategies presents opportunities to develop high-yield "super-crop" varieties with enhanced nutritional value, better processing characteristics, and attributes preferred by consumers. Addressing these challenges is crucial to promote sustainable agriculture and achieve the dual objectives of food security and environmental conservation.
Collapse
Affiliation(s)
- Changfeng Yang
- Frontiers Science Center for Molecular Design Breeding, Key Laboratory of Crop Heterosis and Utilization (MOE), and Beijing Key Laboratory of Crop Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Lichun Huang
- Key Laboratory of Plant Functional Genomics of the Ministry of Education, Zhongshan Biological Breeding Laboratory, Yangzhou Modern Seed Innovation Institute (Gaoyou), Yangzhou University, Yangzhou 225009, China
| | - Bai-Chen Wang
- State Key Laboratory of Forage Breeding-by-Design and Utilization, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China
| | - Yingxin Zhong
- National Technique Innovation Center for Regional Wheat Production/Key Laboratory of Crop Physiology and Ecology in Southern China, Ministry of Agriculture/Nanjing Agricultural University, Nanjing 210095, China
| | - Xiaohui Ma
- Key Laboratory of Plant Molecular Physiology, Institute of Botany, Chinese Academy of Sciences, Beijing, 100093, China
| | - Changquan Zhang
- Key Laboratory of Plant Functional Genomics of the Ministry of Education, Zhongshan Biological Breeding Laboratory, Yangzhou Modern Seed Innovation Institute (Gaoyou), Yangzhou University, Yangzhou 225009, China
| | - Qixin Sun
- Frontiers Science Center for Molecular Design Breeding, Key Laboratory of Crop Heterosis and Utilization (MOE), and Beijing Key Laboratory of Crop Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Yongrui Wu
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology & Ecology, Shanghai 200032, China.
| | - Yingyin Yao
- Frontiers Science Center for Molecular Design Breeding, Key Laboratory of Crop Heterosis and Utilization (MOE), and Beijing Key Laboratory of Crop Genetic Improvement, China Agricultural University, Beijing 100193, China.
| | - Qiaoquan Liu
- Key Laboratory of Plant Functional Genomics of the Ministry of Education, Zhongshan Biological Breeding Laboratory, Yangzhou Modern Seed Innovation Institute (Gaoyou), Yangzhou University, Yangzhou 225009, China.
| |
Collapse
|
5
|
Mauricio H, Abreu JG, Peshkin L. On X-ray Sensitivity in Xenopus Embryogenesis. MICROPUBLICATION BIOLOGY 2025; 2025:10.17912/micropub.biology.001567. [PMID: 40270682 PMCID: PMC12015645 DOI: 10.17912/micropub.biology.001567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/25/2025]
Abstract
We examined the effects of X-ray irradiation on Xenopus laevis , focusing on pre- and post-fertilization exposure. We applied X-ray doses of 10, 50, 100, 250, and 500 Gy. Fifty percent of the 360 eggs irradiated at 250 Gy failed to fertilize, while fertilized eggs developed normally until the gastrula stage. Doses ranging from 10 to 250 Gy caused developmental anomalies. High mortality rates were observed at doses of 100 to 500 Gy. Post-fertilization irradiation at 50 to 100 Gy resulted in 100% lethality, while exposure to 10 Gy led to only 13% lethality, although both exposure levels produced similar types of developmental anomalies compared to pre-fertilization irradiation. This study highlights how the timing and intensity of exposure critically affect embryo viability, especially during the sensitive stages of fertilization and gastrulation. We establish the necessary and sufficient dosage to further investigate the molecular mechanisms of X-ray damage to DNA and protein.
Collapse
Affiliation(s)
- Hugo Mauricio
- Systems Biology, Harvard Medical School
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jose G Abreu
- Systems Biology, Harvard Medical School
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | | |
Collapse
|
6
|
Liskova P, Skalicka P, Dudakova L, Vincent AL. Genotype-Phenotype Correlations in Corneal Dystrophies: Advances in Molecular Genetics and Therapeutic Insights. Clin Exp Ophthalmol 2025; 53:232-245. [PMID: 40079222 PMCID: PMC11962681 DOI: 10.1111/ceo.14516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 02/19/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025]
Abstract
Corneal dystrophies are a group of predominantly rare inherited disorders. They are by definition bilateral, relatively symmetrical, and without systemic involvement, affecting corneal transparency and/or refraction. Traditional classification of corneal dystrophies is based on slit-lamp appearance, affected corneal layer and histological features. Molecular genetics has provided ultimate proof for the existence of distinct corneal dystrophies and discarded duplicates in their terminology. Currently, there are at least 16 genes with identified pathogenic variants implicated in corneal dystrophies. Herein, we summarise contemporary knowledge on genotype-phenotype correlations of corneal dystrophies, including a critical review of some reported variants, along with the understanding of the underlying pathogenic dystrophic process; essential knowledge for the development of targeted therapies.
Collapse
Affiliation(s)
- Petra Liskova
- Department of Ophthalmology, First Faculty of MedicineCharles University and General University Hospital in PraguePragueCzech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of MedicineCharles University and General University Hospital in PraguePragueCzech Republic
| | - Pavlina Skalicka
- Department of Ophthalmology, First Faculty of MedicineCharles University and General University Hospital in PraguePragueCzech Republic
| | - Lubica Dudakova
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of MedicineCharles University and General University Hospital in PraguePragueCzech Republic
| | - Andrea L. Vincent
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health ScienceThe University of AucklandAucklandNew Zealand
- Eye DepartmentGreenlane Clinical Centre, Te Toka Tumai Auckland, Te Whatu Ora, Health New ZealandAucklandNew Zealand
| |
Collapse
|
7
|
Yamada S, Ogawa H, Funato M, Kato M, Nakadate K, Mizukoshi T, Kawakami K, Kobayashi R, Horii T, Hatada I, Sakakibara SI. Induction of MASH-like pathogenesis in the Nwd1 -/- mouse liver. Commun Biol 2025; 8:348. [PMID: 40069352 PMCID: PMC11897295 DOI: 10.1038/s42003-025-07717-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 02/11/2025] [Indexed: 03/15/2025] Open
Abstract
Endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and it's perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Dysfunction of sarco/endoplasmic reticulum calcium ATPase (SERCA2), a key regulator of Ca2+ transport from the cytosol to ER, is associated with the induction of ER stress and lipid droplet formation. We previously identified NACHT and WD repeat domain-containing protein 1 (Nwd1) localized at the ER and mitochondria. However, the physiological significance of Nwd1 outside the brain remains unclear. In this study, we revealed that Nwd1-/- mice exhibited pathological manifestations comparable to MASH. Nwd1 interacts with SERCA2 near ER membranes. Nwd1-/- livers exhibited reduced SERCA2 ATPase activity and a smaller Ca2+ pool in the ER, leading to an exacerbated state of ER stress. These findings highlight the importance of SERCA2 activity mediated by Nwd1 in the pathogenesis of MASH.
Collapse
Affiliation(s)
- Seiya Yamada
- Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan.
- Neuroscience Center, HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
| | - Hayato Ogawa
- Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan
| | - Miona Funato
- Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan
| | - Misaki Kato
- Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan
| | - Kazuhiko Nakadate
- Department of Functional Morphology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
| | - Tomoya Mizukoshi
- Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan
| | - Kiyoharu Kawakami
- Department of Functional Morphology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
| | - Ryosuke Kobayashi
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
| | - Takuro Horii
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
| | - Izuho Hatada
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
- Viral Vector Core, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan
| | - Shin-Ichi Sakakibara
- Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan.
| |
Collapse
|
8
|
Braun AC, Oliveira TC, Thomazini LCD, Argenti G, Kotzian BJ, Machado V, Conte JHM, Zanfir C, Souto ACA, Ulian B, Vidart J, Wajner SM. Induced Types 2 and 3 Deiodinase in Non-Thyroidal Illness Syndrome and the Implications to Critical Illness-Induced Myopathy-A Prospective Cohort Study. Int J Mol Sci 2025; 26:2410. [PMID: 40141055 PMCID: PMC11941936 DOI: 10.3390/ijms26062410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/18/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
Loss of muscle mass and strength is a common condition associated with adverse outcomes in critically ill patients. Here, we determined the correlation between non-thyroidal illness (NTIS) and molecular alterations in the muscle of critically ill individuals. We evaluated deiodinase expression, intramuscular triiodothyronine (T3) levels, and mitochondria and sarcoplasmic reticulum components. The cellular colocalization of the enzymes and its influence on myocytes and genes regulated by T3 were shown, including those of mitochondria. A prospective cohort of 96 patients. Blood and muscular samples were collected on admission to the intensive care unit (ICU), as well as clinical data and ultrasonographic measurements. Patients with NTIS showed increased oxidative stress markers associated with critical illness in muscle biopsy, such as carbonyl content and low sulfhydryl and GSH. The distribution pattern of deiodinases in muscle and its biochemical properties showed significant pathophysiological linkage between NTIS and muscle loss, as type 3-deiodinase (D3) was highly expressed in stem cells, preventing their differentiation in mature myocytes. Despite the high type 2-deiodinase (D2) expression in muscle tissue in the acute phase of critical illness, T3 was unmeasurable in the samples. In this scenario, we also demonstrated impaired expression of glucose transporters GLUT4, IRS1, and 2, which are involved in muscle illness. Here, we provide evidence that altered thyroid hormone metabolism contributes to stem cell dysfunction and further explain the mechanisms underlying critical illness-induced myopathy.
Collapse
Affiliation(s)
- André Cardoso Braun
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Thaliane Carvalho Oliveira
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Ludmilla C. D. Thomazini
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Gustavo Argenti
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Bruno Jaskulski Kotzian
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Valentina Machado
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - João Henrique M. Conte
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Carolina Zanfir
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Amanda C. A. Souto
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Bruna Ulian
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Josi Vidart
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
| | - Simone Magagnin Wajner
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil; (A.C.B.)
- Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Rio Grande do Sul, Brazil
| |
Collapse
|
9
|
Di Mattia M, Sallese M, Lopetuso LR. The interplay between gut microbiota and the unfolded protein response: Implications for intestinal homeostasis preservation and dysbiosis-related diseases. Microb Pathog 2025; 200:107279. [PMID: 39761770 DOI: 10.1016/j.micpath.2025.107279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 11/28/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025]
Abstract
The unfolded protein response (UPR) is a complex intracellular signal transduction system that orchestrates the cellular response during Endoplasmic Reticulum (ER) stress conditions to reestablish cellular proteostasis. If, on one side, prolonged ER stress conditions can lead to programmed cell death and autophagy as a cytoprotective mechanism, on the other, unresolved ER stress and improper UPR activation represent a perilous condition able to trigger or exacerbate inflammatory responses. Notably, intestinal and immune cells experience ER stress physiologically due to their high protein secretory rate. Indeed, there is evidence of UPR's involvement in both physiological and pathological intestinal conditions, while less is known about its bidirectional interaction with gut microbiota. However, gut microbes and their metabolites can influence ER stress and UPR pathways, and, in turn, ER stress conditions can shape gut microbiota composition, with important implications for overall intestinal health. Thus, targeting UPR components is an intriguing strategy for treating ER stress-linked dysbiosis and diseases, particularly intestinal inflammation.
Collapse
Affiliation(s)
- Miriam Di Mattia
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.
| | - Michele Sallese
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Loris Riccardo Lopetuso
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy; Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| |
Collapse
|
10
|
Nar R, Gibbons MD, Perez L, Strouboulis J, Qian Z, Bungert J. TFII-I/GTF2I regulates globin gene expression and stress response in erythroid cells. J Biol Chem 2025; 301:108227. [PMID: 39864622 PMCID: PMC11879681 DOI: 10.1016/j.jbc.2025.108227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 12/28/2024] [Accepted: 01/17/2025] [Indexed: 01/28/2025] Open
Abstract
Transcription factor TFII-I/GTF2I is ubiquitously expressed and has been shown to play a role in the differentiation of hematopoietic cells and in the response to various cellular stressors. We previously demonstrated that TFII-I acts as a repressor of adult β-globin gene transcription and positively regulates the expression of stress response proteins, including ATF3. Here we analyzed the function of TFII-I in TF-1 cells during erythroid differentiation and in response to cellular stress, including unfolded protein response, hypoxia, and oxidative stress. Ablation of TFII-I leads to mild changes in the cell cycle and proliferation of TF-1 cells. Importantly, TFII-I deficiency increased the expression of the adult β-globin gene with a concomitant reduction in the expression of the fetal γ-globin genes during erythropoietin-mediated erythroid differentiation of TF-1 cells. Furthermore, TFII-I regulates genes involved in stress response, including CHOP, Elongin A, ATF3, ATF4, and Grp78, and participates in the apoptotic response to stressors. In summary, the data provide further support for the role of TFII-I in stress response and the regulation of globin genes.
Collapse
Affiliation(s)
- Rukiye Nar
- Department of Biochemistry and Molecular Biology, College of Medicine, Center for Epigenetics, Genetics Institute, UF Health Cancer Center, Powell-Gene Therapy Center, University of Florida, Gainesville, Florida, USA; Department of Medicine, College of Medicine, Center for Epigenetics, Genetics Institute, UF Health Cancer Center, Powell-Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
| | - Matthew D Gibbons
- Department of Biochemistry and Molecular Biology, College of Medicine, Center for Epigenetics, Genetics Institute, UF Health Cancer Center, Powell-Gene Therapy Center, University of Florida, Gainesville, Florida, USA
| | - Leonardo Perez
- Department of Biochemistry and Molecular Biology, College of Medicine, Center for Epigenetics, Genetics Institute, UF Health Cancer Center, Powell-Gene Therapy Center, University of Florida, Gainesville, Florida, USA
| | - John Strouboulis
- Red Cell Haematology, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Zhijian Qian
- Department of Medicine, College of Medicine, Center for Epigenetics, Genetics Institute, UF Health Cancer Center, Powell-Gene Therapy Center, University of Florida, Gainesville, Florida, USA
| | - Jörg Bungert
- Department of Biochemistry and Molecular Biology, College of Medicine, Center for Epigenetics, Genetics Institute, UF Health Cancer Center, Powell-Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
| |
Collapse
|
11
|
Gu L, Lai Z, Zhang C, Liu Z, Huo Y, Qian Y, Wang B, Wang Z, Zhao Z, Hu W, Ma M. (-) - (11R, 12S)-mefloquine ameliorates neuropathic pain by modulating Cx36-ER stress interaction in the pain-related central nervous system in rats. Life Sci 2025; 363:123405. [PMID: 39828229 DOI: 10.1016/j.lfs.2025.123405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/03/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
AIMS To explore the specific molecular and cellular mechanisms of (-) - Mefloquine (one of Mefloquine's enantiomers) in modulating the interaction between Connexin 36 (Cx36) and endoplasmic reticulum stress (ERS) both in rats with CCI-induced neuropathic pain and in tunicamycin-induced ERS cells. MATERIALS AND METHODS The authors conducted chronic constriction injury (CCI) in rats to induce neuropathic pain and established the ERS model in SH-SY5Y cells to mimic the stress state after neuropathic pain. The study employed behavioral tests and various molecular biology techniques, including Western blot analysis, cell transfection, and co-immunoprecipitation (co-IP). KEY FINDINGS In vivo, we found that (-) - MQ treatment alleviated CCI-induced ERS to regulate the cytoplasmic Cx36 by inhibiting the activation of PERK in spinal cord and ATF-6 in hippocampus, thereby ameliorating neuropathic pain significantly. In vitro, (-) - MQ not only promoted Cx36 synthesis in the ER and inhibited the excessive transport of Cx36 from the ER to the Golgi apparatus, but also interrupted the binding of Cx36 with calmodulin (CaM), which led to diminished junction formation as indicated by the reduced over-stacking of Cx36 on the membrane of the ERS-exposed cells. Together, these findings clarified that (-) - MQ could ameliorate neuropathic pain through modulating Cx36-ERS interactions within pain-associated regions of the central nervous system in CCI rats. SIGNIFICANCE This study, for the first time, elucidated the cellular and molecular mechanisms of (-) - MQ in modulating Cx36-ERS interaction in neuropathic pain, thereby providing new therapeutic options for clinical treatment.
Collapse
Affiliation(s)
- Lingling Gu
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China
| | - Zelin Lai
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Cheng Zhang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China
| | - Zhili Liu
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China; Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Yan Huo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Yu Qian
- State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Bingying Wang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China
| | - Zhiru Wang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China
| | - Zheng Zhao
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China.
| | - Wenhao Hu
- State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
| | - Mingliang Ma
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
| |
Collapse
|
12
|
Ghionescu AV, Uta M, Sorop A, Lazar C, Flintoaca-Alexandru PR, Chiritoiu G, Sima L, Petrescu SM, Dima SO, Branza-Nichita N. The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients. J Biomed Sci 2025; 32:11. [PMID: 39838427 PMCID: PMC11752926 DOI: 10.1186/s12929-024-01103-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 11/17/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a major risk for development of hepatocellular carcinoma (HCC), a frequent malignancy with a poor survival rate. HBV infection results in significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling, a contributing factor to carcinogenesis. As part of the UPR, the ER-associated degradation (ERAD) pathway is responsible for removing the burden of misfolded secretory proteins, to re-establish cellular homeostasis. Emerging evidence indicates consistent upregulation of ERAD factors, including members of the ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family in infection and various tumor types. However, the significance of this gene expression pattern in HBV-driven pathology is just beginning to be deciphered. METHODS In this study we quantified the expression of the ERAD factor EDEM3, in a cohort of HCC patients with and without HBV infection, and validated our results by analysis of publically available transcriptomic and microarray data sets. We performed mechanistic studies in HepaRG cells with modulated EDEM3 expression to address UPR, ERAD, autophagy and apoptosis signaling, and their consequences on HBV infection. RESULTS Our work revealed significantly elevated EDEM3 expression in HCC tissues irrespective of HBV infection, while the highest levels were observed in tissues from HBV-infected patients. Investigation of published transcriptomic data sets confirmed EDEM3 upregulation in independent HCC patient cohorts, associated with tumor progression, poor survival prognosis and resistance to therapy. EDEM3-overexpressing hepatic cells exhibited attenuated UPR and activated secretory autophagy, which promoted HBV production. Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death. CONCLUSIONS We provide evidence of major implications of the ERAD pathway in HBV infection and HCC development and progression. Our results suggest that ERAD activation in HBV-infected cells is a protective mechanism against prolonged ER stress, potentially contributing to establishment of chronic HBV infection and promoting tumorigenesis. Developing specific inhibitors for ERAD factors may be an attractive approach to improve efficiency of current antiviral and anticancer therapies.
Collapse
Affiliation(s)
- Alina-Veronica Ghionescu
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania
| | - Mihaela Uta
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania
| | - Catalin Lazar
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania
| | | | - Gabriela Chiritoiu
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Livia Sima
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Stefana-Maria Petrescu
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania.
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania.
| | - Norica Branza-Nichita
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania.
| |
Collapse
|
13
|
Fakir S, Kubra KT, Akhter MS, Uddin MA, Sarker MMR, Siejka A, Barabutis N. Unfolded protein response modulates the effects of GHRH antagonists in experimental models of in vivo and in vitro lung injury. Tissue Barriers 2024:2438974. [PMID: 39653654 DOI: 10.1080/21688370.2024.2438974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/29/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024] Open
Abstract
The development of efficient targeted therapies to ameliorate endothelial disorders is of the utmost need, as evident by the devastating outcomes of the recent pandemic. Recent findings suggest that unfolded protein response (UPR) modulates barrier function. In the current study, we reveal that the aforementioned highly conservative mechanism is involved in the protective effects of growth hormone-releasing hormone antagonists (GHRHAnt) in lung injury, both in vivo and in vitro. In bovine pulmonary artery endothelial cells, UPR suppression counteracted the protective effects of GHRHAnt in lipopolysaccharide (LPS)-induced endothelial hyperpermeability. In mouse lungs, UPR activation enhanced the beneficial effects of GHRHAnt against LPS-induced acute lung injury. Our observations - which are focused on lung endothelial cells and tissues - enhance our knowledge on the mechanisms mediating the barrier function and contribute to the development of novel therapies toward sepsis, direct and indirect lung injury. The effects of UPR modulation on the effects of GHRHAnt in other tissues are unknown, and they are the subject of future investigations.
Collapse
Affiliation(s)
- Saikat Fakir
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
| | - Khadeja-Tul Kubra
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
| | - Mohammad Shohel Akhter
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
| | - Mohammad Afaz Uddin
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
| | - Md Matiur Rahman Sarker
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
| | - Agnieszka Siejka
- Department of Clinical Endocrinology, Medical University of Lodz, Lodz, Poland
| | - Nektarios Barabutis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
| |
Collapse
|
14
|
Abhirami N, Ayyappan JP. Cardioprotective effect of Robinin ameliorates Endoplasmic Reticulum Stress and Apoptosis in H9c2 cells. Cell Biochem Biophys 2024; 82:3681-3694. [PMID: 39095567 DOI: 10.1007/s12013-024-01456-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2024] [Indexed: 08/04/2024]
Abstract
Robinin is one of the glycosyloxyflavones that has been less explored for its therapeutic application, especially in the field of CVD. Herein, we explored the cardioprotective efficacy of Robinin by using H2O2 and Doxorubicin (DOX) - treated H9c2 cells as an in vitro model. H2O2 and DOX treatment resulted in severe cellular damage to the cardiomyocytes, which was followed by apoptosis. Apoptosis and nuclear morphology were analysed through Hoechst 33342 and AO/EB staining. qPCR was employed to detect the expression of apoptosis as well as ERS-related markers. Reactive oxygen species (ROS) generation was observed using DCFH-DA staining and FACS analysis. Signaling pathways involved were analysed using Western blot. Robinin pre-treatment considerably decreased the apoptotic rate by boosting the endogenous anti-oxidative activity and lowering the activity of Malonaldehyde and Lactate dehydrogenase enzyme. Robinin also inhibited the generation of ROS. Robinin reduced the expression of ERS-associated genes and proteins, thereby decreasing apoptosis-related proteins. Upon comparing the cardioprotective effect of Robinin with a known cardioprotective agent Dexrazoxane (DEX) it was revealed that DEX has more cardioprotective effect against DOX than H2O2-induced stress, while Robinin showed a significant protective effect against both H2O2 and DOX induced stress.
Collapse
Affiliation(s)
- N Abhirami
- Translational Nanomedicine and Lifestyle Disease Research Laboratory, Department of Biochemistry, University of Kerala, Kariavattom campus, Thiruvananthapuram, 695034, Kerala, India
| | - Janeesh Plakkal Ayyappan
- Translational Nanomedicine and Lifestyle Disease Research Laboratory, Department of Biochemistry, University of Kerala, Kariavattom campus, Thiruvananthapuram, 695034, Kerala, India.
- Centre for Advanced Cancer Research, Department of Biochemistry, University of Kerala, Kariavattom campus, Thiruvananthapuram, 695034, Kerala, India.
| |
Collapse
|
15
|
Makio T, Chen J, Simmen T. ER stress as a sentinel mechanism for ER Ca 2+ homeostasis. Cell Calcium 2024; 124:102961. [PMID: 39471738 DOI: 10.1016/j.ceca.2024.102961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 11/01/2024]
Abstract
Endoplasmic reticulum (ER) stress is triggered upon the interference with oxidative protein folding that aims to produce fully folded, disulfide-bonded and glycosylated proteins, which are then competent to exit the ER. Many of the enzymes catalyzing this process require the binding of Ca2+ ions, including the chaperones BiP/GRP78, calnexin and calreticulin. The induction of ER stress with a variety of drugs interferes with chaperone Ca2+ binding, increases cytosolic Ca2+through the opening of ER Ca2+ channels, and activates store-operated Ca2+ entry (SOCE). Posttranslational modifications (PTMs) of the ER Ca2+ handling proteins through ER stress-dependent phosphorylation or oxidation control these mechanisms, as demonstrated in the case of the sarco/endoplasmic reticulum ATPase (SERCA), inositol 1,4,5 trisphosphate receptors (IP3Rs) or stromal interaction molecule 1 (STIM1). Their aim is to restore ER Ca2+ homeostasis but also to increase Ca2+ transfer from the ER to mitochondria during ER stress. This latter function boosts ER bioenergetics, but also triggers apoptosis if ER Ca2+ signaling persists. ER Ca2+ toolkit oxidative modifications upon ER stress can occur within the ER lumen or in the adjacent cytosol. Enzymes involved in this redox control include ER oxidoreductin 1 (ERO1) or the thioredoxin-family protein disulfide isomerases (PDI) and ERp57. A tight, but adaptive connection between ER Ca2+ content, ER stress and mitochondrial readouts allows for the proper functioning of many tissues, including skeletal muscle, the liver, and the pancreas, where ER stress either maintains or compromises their function, depending on its extent and context. Upon mutation of key regulators of ER Ca2+ signaling, diseases such as muscular defects (e.g., from mutated selenoprotein N, SEPN1/SELENON), or diabetes (e.g., from mutated PERK) are the result.
Collapse
Affiliation(s)
- Tadashi Makio
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada
| | - Junsheng Chen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada.
| |
Collapse
|
16
|
Mahapatra PP, Ahmed S. Fission yeast Bsd1 is required for ER stress response in Ire1 independent manner. Mol Biol Rep 2024; 52:19. [PMID: 39601909 DOI: 10.1007/s11033-024-10121-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Endoplasmic reticulum plays a central role in protein folding and cellular detoxification. NEDD4, a HECT E3 ubiquitin ligase, has been implicated in endoplasmic reticulum stress in humans. In this study, we have explored the role of S. pombe Bsd1, an ortholog of mammalian Ndfip1 (NEDD4 interacting protein 1) in tunicamycin-induced stress response pathway. METHODS AND RESULTS Bsd1, an ortholog of mammalian NEDD4 interacting protein 1 (Ndfip1) plays a protective role against tunicamycin-induced ER stress. The confocal microscopy using GFP tagged Bsd1 revealed its localization to the membrane, with a more pronounced signal in the presence of tunicamycin. Additionally, the expression analysis showed a two-fold increase in the expression of Bsd1 after 4 h exposure to tunicamycin. Furthermore, acridine orange/ ethidium bromide staining and MTT assay revealed an increase in apoptotic cell death in bsd1Δ as compared to wild type cells after treatment with ER stressors. Compared to the wild type, we observed punctate FM4-64 staining in bsd1Δ cells in the presence of tunicamycin suggesting a significant loss of vacuolar structures. In a genetic interaction analysis, we observed enhanced sensitivity of tunicamycin in bsd1Δ ire1Δ double mutant as compared to each single mutant, suggesting the role of Bsd1 in the tunicamycin-induced ER stress response might be independent of the Ire1 pathway. CONCLUSION Our study has implicated the role of fission yeast Bsd1 in ER stress response in an Ire1 independent pathway. Further, we have shown its role in apoptotic cell death and the maintenance of vacuolar structures.
Collapse
Affiliation(s)
- Pinaki Prasad Mahapatra
- Biochemistry and Structural Biology Division, CSIR- Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shakil Ahmed
- Biochemistry and Structural Biology Division, CSIR- Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
| |
Collapse
|
17
|
Hu D, Yang Y, Fang L, Fan S, Lin L, Luo P, Xiong Y, Su Y. Isoliquiritigenin induced hepatotoxicity and endoplasmic reticulum stress in zebrafish embryos. Sci Rep 2024; 14:28256. [PMID: 39548255 PMCID: PMC11568227 DOI: 10.1038/s41598-024-79016-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024] Open
Abstract
Isoliquiritigenin (ISL), a naturally occurring flavonoid derived from licorice root, exhibits antioxidant, anticancer, anti-inflammatory, and anti-allergic properties, and is frequently detected in both environmental and human samples. Previous studies from our lab have demonstrated that ISL exposure can lead to developmental deformities and aberrant immune responses. However, the molecular mechanisms underlying ISL toxicity in zebrafish embryos remain incompletely elucidated. Therefore, this study aimed to elucidate the effects of ISL exposure on endoplasmic reticulum (ER) stress in zebrafish embryos by assessing the expression levels of ER stress markers HSPA5 and CHOP, along with associated apoptosis factors, under various ISL concentrations, with tunicamycin (TM) serving as a positive control. Furthermore, targeted analyses of ER stress-related pathways were conducted using RNA transcriptome sequencing, and the up-regulated gene was verified by western blot. The results revealed that ISL exposure significantly elevated the expression levels of HSPA5 and CHOP, concomitantly activating ER stress pathways, including pPERK-eIF2α-ATF4 and ATF6 pathways in zebrafish embryos. These findings suggest that the activation of endoplasmic reticulum stress signaling pathways may contribute to the developmental deformities observed in zebrafish embryos following ISL exposure, thereby highlighting the potential ecological risks associated with ISL usage.
Collapse
Affiliation(s)
- Deliang Hu
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China
| | - Yuqing Yang
- Department of Pharmacy , Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, P. R. China
| | - Lei Fang
- Emergency department, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, Jiangxi, P.R. China
| | - Shijie Fan
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China
| | - Ling Lin
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China
| | - Puying Luo
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China
| | - Yuanhuan Xiong
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China.
| | - Yufang Su
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China.
| |
Collapse
|
18
|
Luchetti N, Smith KM, Matarrese MAG, Loppini A, Filippi S, Chiodo L. A statistical mechanics investigation of unfolded protein response across organisms. Sci Rep 2024; 14:27658. [PMID: 39532983 PMCID: PMC11557608 DOI: 10.1038/s41598-024-79086-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Living systems rely on coordinated molecular interactions, especially those related to gene expression and protein activity. The Unfolded Protein Response is a crucial mechanism in eukaryotic cells, activated when unfolded proteins exceed a critical threshold. It maintains cell homeostasis by enhancing protein folding, initiating quality control, and activating degradation pathways when damage is irreversible. This response functions as a dynamic signaling network, with proteins as nodes and their interactions as edges. We analyze these protein-protein networks across different organisms to understand their intricate intra-cellular interactions and behaviors. In this work, analyzing twelve organisms, we assess how fundamental measures in network theory can individuate seed proteins and specific pathways across organisms. We employ network robustness to evaluate and compare the strength of the investigated protein-protein interaction networks, and the structural controllability of complex networks to find and compare the sets of driver nodes necessary to control the overall networks. We find that network measures are related to phylogenetics, and advanced network methods can identify main pathways of significance in the complete Unfolded Protein Response mechanism.
Collapse
Affiliation(s)
- Nicole Luchetti
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy.
- Center for Life Nano- & Neuro-Science, Italian Institute of Technology, Viale Regina Elena 291, Rome, 00161, Italy.
| | - Keith M Smith
- Computer and Information Sciences, University of Strathclyde, 26 Richmond Street, Glasgow, G1 1XH, United Kingdom
| | - Margherita A G Matarrese
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy
| | - Alessandro Loppini
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy
| | - Simonetta Filippi
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy.
- National Institute of Optics, National Research Council, Largo Enrico Fermi 6, Florence, 50125, Italy.
- International Center for Relativistic Astrophysics Network, Piazza della Repubblica 10, Pescara, 65122, Italy.
| | - Letizia Chiodo
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy
| |
Collapse
|
19
|
Fiorini MR, Dilliott AA, Thomas RA, Farhan SMK. Transcriptomics of Human Brain Tissue in Parkinson's Disease: a Comparison of Bulk and Single-cell RNA Sequencing. Mol Neurobiol 2024; 61:8996-9015. [PMID: 38578357 PMCID: PMC11496323 DOI: 10.1007/s12035-024-04124-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/12/2024] [Indexed: 04/06/2024]
Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease leading to motor dysfunction and, in some cases, dementia. Transcriptome analysis is one promising approach for characterizing PD and other neurodegenerative disorders by informing how specific disease events influence gene expression and contribute to pathogenesis. With the emergence of single-cell and single-nucleus RNA sequencing (scnRNA-seq) technologies, the transcriptional landscape of neurodegenerative diseases can now be described at the cellular level. As the application of scnRNA-seq is becoming routine, it calls to question how results at a single-cell resolution compare to those obtained from RNA sequencing of whole tissues (bulk RNA-seq), whether the findings are compatible, and how the assays are complimentary for unraveling the elusive transcriptional changes that drive neurodegenerative disease. Herein, we review the studies that have leveraged RNA-seq technologies to investigate PD. Through the integration of bulk and scnRNA-seq findings from human, post-mortem brain tissue, we use the PD literature as a case study to evaluate the compatibility of the results generated from each assay and demonstrate the complementarity of the sequencing technologies. Finally, through the lens of the PD transcriptomic literature, we evaluate the current feasibility of bulk and scnRNA-seq technologies to illustrate the necessity of both technologies for achieving a comprehensive insight into the mechanism by which gene expression promotes neurodegenerative disease. We conclude that the continued application of both assays will provide the greatest insight into neurodegenerative disease pathology, providing both cell-specific and whole-tissue level information.
Collapse
Affiliation(s)
- Michael R Fiorini
- The Montreal Neurological Institute-Hospital, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Allison A Dilliott
- The Montreal Neurological Institute-Hospital, Montreal, QC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Rhalena A Thomas
- The Montreal Neurological Institute-Hospital, Montreal, QC, Canada.
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
| | - Sali M K Farhan
- The Montreal Neurological Institute-Hospital, Montreal, QC, Canada.
- Department of Human Genetics, McGill University, Montreal, QC, Canada.
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
| |
Collapse
|
20
|
Tian L, Andrews C, Yan Q, Yang JJ. Molecular regulation of calcium-sensing receptor (CaSR)-mediated signaling. Chronic Dis Transl Med 2024; 10:167-194. [PMID: 39027195 PMCID: PMC11252437 DOI: 10.1002/cdt3.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/29/2024] [Accepted: 04/09/2024] [Indexed: 07/20/2024] Open
Abstract
Calcium-sensing receptor (CaSR), a family C G-protein-coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L-Trp and L-Phe), small peptides, anions (e.g., HCO3 - and PO4 3-), and pH. CaSR-mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.
Collapse
Affiliation(s)
- Li Tian
- Department of Chemistry, Center for Diagnostics and Therapeutics, Advanced Translational Imaging FacilityGeorgia State UniversityAtlantaGeorgiaUSA
| | - Corey Andrews
- Department of Chemistry, Center for Diagnostics and Therapeutics, Advanced Translational Imaging FacilityGeorgia State UniversityAtlantaGeorgiaUSA
| | - Qiuyun Yan
- Department of Chemistry, Center for Diagnostics and Therapeutics, Advanced Translational Imaging FacilityGeorgia State UniversityAtlantaGeorgiaUSA
| | - Jenny J. Yang
- Department of Chemistry, Center for Diagnostics and Therapeutics, Advanced Translational Imaging FacilityGeorgia State UniversityAtlantaGeorgiaUSA
| |
Collapse
|
21
|
Wong AM, Budin I. Organelle-Targeted Laurdans Measure Heterogeneity in Subcellular Membranes and Their Responses to Saturated Lipid Stress. ACS Chem Biol 2024; 19:1773-1785. [PMID: 39069657 PMCID: PMC11670155 DOI: 10.1021/acschembio.4c00249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Organelles feature characteristic lipid compositions that lead to differences in membrane properties. In cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to lipid packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells; therefore, it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out the membrane packing of individual cellular organelles. The set of organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes, and Golgi compartments with high specificity while retaining the spectral resolution needed to detect biological changes in membrane ordering. We show that ratiometric imaging with OTLs can resolve membrane heterogeneity within organelles as well as changes in lipid packing resulting from inhibition of trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While the ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application in interrogating lipid dysregulation.
Collapse
Affiliation(s)
- Adrian M. Wong
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| | - Itay Budin
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| |
Collapse
|
22
|
Sun M, Zhang X, Tan B, Zhang Q, Zhao X, Dong D. Potential role of endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity-an update. Front Pharmacol 2024; 15:1415108. [PMID: 39188945 PMCID: PMC11345228 DOI: 10.3389/fphar.2024.1415108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/01/2024] [Indexed: 08/28/2024] Open
Abstract
As a chemotherapy agent, doxorubicin is used to combat cancer. However, cardiotoxicity has limited its use. The existing strategies fail to eliminate doxorubicin-induced cardiotoxicity, and an in-depth exploration of its pathogenesis is in urgent need to address the issue. Endoplasmic reticulum stress (ERS) occurs when Endoplasmic Reticulum (ER) dysfunction results in the accumulation of unfolded or misfolded proteins. Adaptive ERS helps regulate protein synthesis to maintain cellular homeostasis, while prolonged ERS stimulation may induce cell apoptosis, leading to dysfunction and damage to tissue and organs. Numerous studies on doxorubicin-induced cardiotoxicity strongly link excessive activation of the ERS to mechanisms including oxidative stress, calcium imbalance, autophagy, ubiquitination, and apoptosis. The researchers also found several clinical drugs, chemical compounds, phytochemicals, and miRNAs inhibited doxorubicin-induced cardiotoxicity by targeting ERS. The present review aims to outline the interactions between ERS and other mechanisms in doxorubicin-induced cardiotoxicity and summarize ERS's role in this type of cardiotoxicity. Additionally, the review enumerates several clinical drugs, phytochemicals, chemical compounds, and miRNAs targeting ERS for considering therapeutic regimens that address doxorubicin-induced cardiotoxicity.
Collapse
Affiliation(s)
- Mingli Sun
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Xin Zhang
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Boxuan Tan
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Qingya Zhang
- Innovation Institute, China Medical University, Shenyang, Liaoning, China
| | - Xiaopeng Zhao
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Dan Dong
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
23
|
Chakrabarty A, Newey SE, Promi MM, Agbetiameh BK, Munro D, Brodersen PJN, Gothard G, Mahfooz K, Mengual JP, Vyazovskiy VV, Akerman CJ. sUPRa is a dual-color reporter for unbiased quantification of the unfolded protein response with cellular resolution. Sci Rep 2024; 14:14990. [PMID: 38951511 PMCID: PMC11217371 DOI: 10.1038/s41598-024-65611-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 06/21/2024] [Indexed: 07/03/2024] Open
Abstract
The unfolded protein response (UPR) maintains proteostasis upon endoplasmic reticulum (ER) stress, and is initiated by a range of physiological and pathological processes. While there have been advances in developing fluorescent reporters for monitoring individual signaling pathways of the UPR, this approach may not capture a cell's overall UPR activity. Here we describe a novel sensor of UPR activity, sUPRa, which is designed to report the global UPR. sUPRa displays excellent response characteristics, outperforms reporters of individual UPR pathways in terms of sensitivity and kinetics, and responds to a range of different ER stress stimuli. Furthermore, sUPRa's dual promoter and fluorescent protein design ensures that both UPR-active and inactive cells are detected, and controls for reporter copy number. Using sUPRa, we reveal UPR activation in layer 2/3 pyramidal neurons of mouse cerebral cortex following a period of sleep deprivation. sUPRa affords new opportunities for quantifying physiological UPR activity with cellular resolution.
Collapse
Affiliation(s)
- Atreyi Chakrabarty
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Sarah E Newey
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Maisha M Promi
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Belinda K Agbetiameh
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Daniella Munro
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Paul J N Brodersen
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Gemma Gothard
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Kashif Mahfooz
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
| | - Jose P Mengual
- Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Road, Oxford, OX1 3PT, UK
| | - Vladyslav V Vyazovskiy
- Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Road, Oxford, OX1 3PT, UK
| | - Colin J Akerman
- Department of Pharmacology, University of Oxford, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
| |
Collapse
|
24
|
Ahuja N, Gupta S, Arora R, Bhagyaraj E, Tiwari D, Kumar S, Gupta P. Nr1h4 and Thrb ameliorate ER stress and provide protection in the MPTP mouse model of Parkinson's. Life Sci Alliance 2024; 7:e202302416. [PMID: 38609183 PMCID: PMC11015051 DOI: 10.26508/lsa.202302416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Elevated ER stress has been linked to the pathogenesis of several disease conditions including neurodegeneration. In this study, we have holistically determined the differential expression of all the nuclear receptors (NRs) in the presence of classical ER stress inducers. Activation of Nr1h4 and Thrb by their cognate ligands (GW4064 and T3) ameliorates the tunicamycin (TM)-induced expression of ER stress genes. A combination of both ligands is effective in mitigating cell death induced by TM. Further exploration of their protective effects in the Parkinson's disease (PD) model shows that they reduce MPP+-induced dissipation of mitochondrial membrane potential and ROS generation in an in vitro PD model in neuronal cells. Furthermore, the generation of an experimental murine PD model reveals that simultaneous treatment of GW4064 and T3 protects mice from ER stress, dopaminergic cell death, and functional deficits in the MPTP mouse model of PD. Thus, activation of Nr1h4 and Thrb by their respective ligands plays an indispensable role in ER stress amelioration and mounts protective effects in the MPTP mouse model of PD.
Collapse
Affiliation(s)
- Nancy Ahuja
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Shalini Gupta
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Rashmi Arora
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ella Bhagyaraj
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Drishti Tiwari
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Sumit Kumar
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Pawan Gupta
- Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| |
Collapse
|
25
|
Posadas N, Conaco C. Gene networks governing the response of a calcareous sponge to future ocean conditions reveal lineage-specific XBP1 regulation of the unfolded protein response. Ecol Evol 2024; 14:e11652. [PMID: 38952658 PMCID: PMC11214833 DOI: 10.1002/ece3.11652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 07/03/2024] Open
Abstract
Marine sponges are predicted to be winners in the future ocean due to their exemplary adaptive capacity. However, while many sponge groups exhibit tolerance to a wide range of environmental insults, calcifying sponges may be more susceptible to thermo-acidic stress. To describe the gene regulatory networks that govern the stress response of the calcareous sponge, Leucetta chagosensis (class Calcarea, order Clathrinida), individuals were subjected to warming and acidification conditions based on the climate models for 2100. Transcriptome analysis and gene co-expression network reconstruction revealed that the unfolded protein response (UPR) was activated under thermo-acidic stress. Among the upregulated genes were two lineage-specific homologs of X-box binding protein 1 (XBP1), a transcription factor that activates the UPR. Alternative dimerization between these XBP1 gene products suggests a clathrinid-specific mechanism to reversibly sequester the transcription factor into an inactive form, enabling the rapid regulation of pathways linked to the UPR in clathrinid calcareous sponges. Our findings support the idea that transcription factor duplication events may refine evolutionarily conserved molecular pathways and contribute to ecological success.
Collapse
Affiliation(s)
- Niño Posadas
- Marine Science Institute, University of the Philippines DilimanQuezon CityPhilippines
- Present address:
Centre for Chromosome Biology, School of Biological and Chemical SciencesUniversity of GalwayGalwayIreland
| | - Cecilia Conaco
- Marine Science Institute, University of the Philippines DilimanQuezon CityPhilippines
| |
Collapse
|
26
|
Shao Y, Zheng L, Jiang Y. Cadmium toxicity and autophagy: a review. Biometals 2024; 37:609-629. [PMID: 38277035 DOI: 10.1007/s10534-023-00581-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 12/31/2023] [Indexed: 01/27/2024]
Abstract
Cadmium (Cd) is an important environmental pollutant that poses a threat to human health and represents a critical component of air pollutants, food sources, and cigarette smoke. Cd is a known carcinogen and has toxic effects on the environment and various organs in humans. Heavy metals within an organism are difficult to biodegrade, and those that enter the respiratory tract are difficult to remove. Autophagy is a key mechanism for counteracting extracellular (microorganisms and foreign bodies) or intracellular (damaged organelles and proteins that cannot be degraded by the proteasome) stress and represents a self-protective mechanism for eukaryotes against heavy metal toxicity. Autophagy maintains cellular homeostasis by isolating and gathering information about foreign chemicals associated with other molecular events. However, autophagy may trigger cell death under certain pathological conditions, including cancer. Autophagy dysfunction is one of the main mechanisms underlying Cd-induced cytotoxicity. In this review, the toxic effects of Cd-induced autophagy on different human organ systems were evaluated, with a focus on hepatotoxicity, nephrotoxicity, respiratory toxicity, and neurotoxicity. This review also highlighted the classical molecular pathways of Cd-induced autophagy, including the ROS-dependent signaling pathways, endoplasmic reticulum (ER) stress pathway, Mammalian target of rapamycin (mTOR) pathway, Beclin-1 and Bcl-2 family, and recently identified molecules associated with Cd. Moreover, research directions for Cd toxicity regarding autophagic function were proposed. This review presents the latest theories to comprehensively reveal autophagy behavior in response to Cd toxicity and proposes novel potential autophagy-targeted prevention and treatment strategies for Cd toxicity and Cd-associated diseases in humans.
Collapse
Affiliation(s)
- Yueting Shao
- Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, 511436, China
- School of Public Health, Guangzhou Medical University, Guangzhou, 511436, China
| | - Liting Zheng
- Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yiguo Jiang
- Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, 511436, China.
- School of Public Health, Guangzhou Medical University, Guangzhou, 511436, China.
| |
Collapse
|
27
|
Yin J, Fu X, Luo Y, Leng Y, Ao L, Xie C. A Narrative Review of Diabetic Macroangiopathy: From Molecular Mechanism to Therapeutic Approaches. Diabetes Ther 2024; 15:585-609. [PMID: 38302838 PMCID: PMC10942953 DOI: 10.1007/s13300-024-01532-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/11/2024] [Indexed: 02/03/2024] Open
Abstract
Diabetic macroangiopathy, a prevalent and severe complication of diabetes mellitus, significantly contributes to the increased morbidity and mortality rates among affected individuals. This complex disorder involves multifaceted molecular mechanisms that lead to the dysfunction and damage of large blood vessels, including atherosclerosis (AS) and peripheral arterial disease. Understanding the intricate pathways underlying the development and progression of diabetic macroangiopathy is crucial for the development of effective therapeutic interventions. This review aims to shed light on the molecular mechanism implicated in the pathogenesis of diabetic macroangiopathy. We delve into the intricate interplay of chronic inflammation, oxidative stress, endothelial dysfunction, and dysregulated angiogenesis, all of which contribute to the vascular complications observed in this disorder. By exploring the molecular mechanism involved in the disease we provide insight into potential therapeutic targets and strategies. Moreover, we discuss the current therapeutic approaches used for treating diabetic macroangiopathy, including glycemic control, lipid-lowering agents, and vascular interventions.
Collapse
Affiliation(s)
- Jiacheng Yin
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Xiaoxu Fu
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Yue Luo
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Yuling Leng
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Lianjun Ao
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
| |
Collapse
|
28
|
Zhang L, Tang F. Molecular mechanism of Serratia marcescens Bizio infection in Reticulitermes chinensis Snyder based on full-length SMRT transcriptome sequencing. BULLETIN OF ENTOMOLOGICAL RESEARCH 2024:1-13. [PMID: 38328866 DOI: 10.1017/s000748532300072x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Reticulitermes chinensis Snyder is an important pest in forestry and construction and is widely distributed in China. We found that Serratia marcescens Bizio strain SM1 has insecticidal activity to R. chinensis, but the pathogenic mechanism of SM1 to R. chinensis is not clear. Therefore, full-length transcriptome sequencing was performed on R. chinensis infected with SM1 and the control group. A total of 230 differentially expressed genes were identified by comparing SM1 infection group and the control group, among which 103 were downregulated and 127 were upregulated. We found downregulated genes in nine metabolic pathway categories, among which carbohydrate metabolism had the most downregulated genes, followed by energy metabolism and amino acid metabolism. We also found that some downregulated genes were related to pattern recognition receptors, cellular immunity, and humoral immunity, indicating that R. chinensis immunity was negatively affected by SM1 infection. In addition, some genes in signal transduction and genetic information processing pathways were downregulated. In this study, high-throughput full-length transcriptome analysis was used to analyse the pathogenic mechanism of SM1 to R. chinensis. The results of this study provide useful information for exploring the relationship between SM1 and R. chinensis, and provide theoretical support for the future application of SM1 and the prevention and treatment of R. chinensis.
Collapse
Affiliation(s)
- Ling Zhang
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, People's Republic of China
- College of Forestry, Nanjing Forestry University, Nanjing 210037, People's Republic of China
| | - Fang Tang
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, People's Republic of China
- College of Forestry, Nanjing Forestry University, Nanjing 210037, People's Republic of China
| |
Collapse
|
29
|
Zhang X, Tang X, Xu J, Zheng Y, Lin J, Zou H. Transcriptome analysis reveals dysfunction of the endoplasmic reticulum protein processing in the sonic muscle of small yellow croaker (Larimichthys polyactis) following noise exposure. MARINE ENVIRONMENTAL RESEARCH 2024; 194:106299. [PMID: 38154196 DOI: 10.1016/j.marenvres.2023.106299] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 10/25/2023] [Accepted: 12/05/2023] [Indexed: 12/30/2023]
Abstract
Noise pollution is increasingly prevalent in aquatic ecosystems, causing detrimental effects on growth and behavior of marine fishes. The physiological responses of fish to underwater noise are poorly understood. In this study, we used RNA-sequencing (RNA-seq) to study the transcriptome of the sonic muscle in small yellow croaker (Larimichthys polyactis) after exposure to a 120 dB noise for 30 min. The behavioral experiment revealed that noise exposure resulted in accelerated tail swimming behavior at the beginning of the exposure period, followed by loss of balance at the end of experiment. Transcriptomic analysis found that most highly expressed genes in the sonic muscle, including parvalbumin, slc25a4, and troponin C were related with energy metabolism and locomotor function. Further, a total of 1261 differentially expressed genes (DEGs) were identified, including 284 up-regulated and 977 down-regulated genes in the noise exposure group compared with the control group. Gene ontology (GO) analysis indicated that the most enriched categories of DEGs included protein folding and response to unfolding protein. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found over-represented pathways including protein processing in the endoplasmic reticulum, chaperones and folding catalysts, as well as arginine and proline metabolism. Specifically, many genes related to fatty acid and collagen metabolism were up-regulated in the noise exposure group. Taken together, our results indicate that exposure to noise stressors alters the swimming behavior of croaker, inducing endoplasmic reticulum stress, disrupting lipid metabolism, and causing collagen degradation in the sonic muscle of L. polyactis.
Collapse
Affiliation(s)
- Xuguang Zhang
- Engineering Technology Research Center of Marine Ranching, College of Marine Ecology and Environment, Shanghai Ocean University, Shanghai, 201306, China
| | - Xianming Tang
- Hainan Provincial Key Laboratory of Tropical Maricultural Technology, Hainan Academy of Ocean and Fisheries Sciences, Haikou, Hainan, 571126, China
| | - Jianan Xu
- Shanghai Aquatic Wildlife Conservation Research Center, Shanghai, 200003, China
| | - Yueping Zheng
- Shanghai Aquatic Wildlife Conservation Research Center, Shanghai, 200003, China
| | - Jun Lin
- Engineering Technology Research Center of Marine Ranching, College of Marine Ecology and Environment, Shanghai Ocean University, Shanghai, 201306, China.
| | - Huafeng Zou
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China; National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China.
| |
Collapse
|
30
|
Li LD, Zhou Y, Shi SF. Identification and characterization of biomarkers associated with endoplasmic reticulum protein processing in cerebral ischemia-reperfusion injury. PeerJ 2024; 12:e16707. [PMID: 38188159 PMCID: PMC10768662 DOI: 10.7717/peerj.16707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
Background Cerebral ischemia (CI), ranking as the second leading global cause of death, is frequently treated by reestablishing blood flow and oxygenation. Paradoxically, this reperfusion can intensify tissue damage, leading to CI-reperfusion injury. This research sought to uncover biomarkers pertaining to protein processing in the endoplasmic reticulum (PER) during CI-reperfusion injury. Methods We utilized the Gene Expression Omnibus (GEO) dataset GSE163614 to discern differentially expressed genes (DEGs) and single out PER-related DEGs. The functions and pathways of these PER-related DEGs were identified via Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Core genes were pinpointed through protein-protein interaction (PPI) networks. Subsequent to this, genes with diagnostic relevance were distinguished using external validation datasets. A single-sample gene-set enrichment analysis (ssGSEA) was undertaken to pinpoint genes with strong associations to hypoxia and apoptosis, suggesting their potential roles as primary inducers of apoptosis in hypoxic conditions during ischemia-reperfusion injuries. Results Our study demonstrated that PER-related genes, specifically ADCY5, CAMK2A, PLCB1, NTRK2, and DLG4, were markedly down-regulated in models, exhibiting a robust association with hypoxia and apoptosis. Conclusion The data indicates that ADCY5, CAMK2A, PLCB1, NTRK2, and DLG4 could be pivotal genes responsible for triggering apoptosis in hypoxic environments during CI-reperfusion injury.
Collapse
Affiliation(s)
- Liang-da Li
- Department of Neurology, The People’s Hospital Affiliated to Ningbo University, Ningbo, Zhejiang, China
| | - Yue Zhou
- Department of Neurology, The People’s Hospital Affiliated to Ningbo University, Ningbo, Zhejiang, China
| | - Shan-fen Shi
- Department of Rheumatology, The People’s Hospital Affiliated to Ningbo University, Ningbo, Zhejiang, China
| |
Collapse
|
31
|
Zhang C, Jiao B, Cao X, Zhang W, Yu S, Zhang K, Zhang M, Zhang X. NTRK1-mediated protection against manganese-induced neurotoxicity and cell apoptosis via IGF2 in SH-SY5Y cells. Biomed Pharmacother 2023; 169:115889. [PMID: 37984302 DOI: 10.1016/j.biopha.2023.115889] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/27/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Excessive manganese (Mn) exposure has been linked to neurotoxicity, cognitive impairments. Neurotrophic Receptor Kinase 1 (NTRK1) encodes Tropomyosin kinase A (TrkA), a neurotrophic receptor, as a mediator of neuron differentiation and survival. Insulin-like growth factor 2 (IGF2), a pivotal member of the insulin gene family, plays a crucial role in brain development and neuroprotection. Despite this knowledge, the precise mechanisms through which NTRK1 and IGF2 influence cell responses to Mn-induced neuronal damage remain elusive. METHODS Cell apoptosis was assessed using CCK8, TUNEL staining, and Western blot analysis of cleaved Caspase-3. Lentiviral vectors facilitated NTRK1 overexpression, while small interfering RNAs (siRNAs) facilitated IGF2 knockdown. Real-time Quantitative PCR (qPCR) determined gene expression levels, while Western blotting measured protein expression. RESULTS The study reveals that NTRK1 inhibits MnCl2-induced apoptosis in SH-SY5Y cells. NTRK1 overexpression significantly upregulated IGF2 expression, and subsequent siRNA-IGF2 experiments confirmed IGF2's pivotal role in NTRK1-mediated neuroprotection. Notably, the study identifies that NTRK1 regulates the expression of IGF2 in the neuroprotective mechanism with the involvement of ER stress pathways. DISCUSSION The study reveals NTRK1's neuroprotective role via IGF2 against Mn-induced neurotoxicity and ER stress modulation in SH-SY5Y cells. These findings offer insights into potential therapies for neurodegenerative disorders related to Mn exposure and NTRK1 dysfunction, driving future research in this domain.
Collapse
Affiliation(s)
- Caixia Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bo Jiao
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xueqin Cao
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Wencui Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shangchen Yu
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaiwen Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mi Zhang
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China.
| | - Xianwei Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
| |
Collapse
|
32
|
Jiao Y, Zhang X, Yang H, Ma H, Zou J. Mesoporous tantalum oxide nanomaterials induced cardiovascular endothelial cell apoptosis via mitochondrial-endoplasmic reticulum stress apoptotic pathway. Drug Deliv 2023; 30:108-120. [PMID: 36533874 PMCID: PMC9788694 DOI: 10.1080/10717544.2022.2147251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Along with its wide range of potential applications, human exposure to mesoporous tantalum oxide nanomaterials (PEG@mTa2O5) has substantially risen. Accumulative toxic investigations have shown the PEG@mTa2O5 intake and cardiovascular diseases (CVD). Endothelial cell death is crucial in the onset and development of atherosclerosis. Still, the molecular mechanism connecting PEG@mTa2O5 and endothelium apoptosis remains unclear. Herein, we studied the absorption and toxic action of mesoporous tantalum oxide (mTa2O5) nanomaterials with polyethylene glycol (PEG) utilizing human cardio microvascular endothelial cells (HCMECs). We also showed that PEG@mTa2O5 promoted apoptosis in endothelial cells using flow cytometry and AO-EB staining. In conjunction with the ultrastructure modifications, PEG@mTa2O5 prompted mitochondrial ROS production, cytosolic Ca2+ overload, ΔΨm collapse, and ER stress verified by elevated ER-Tracker staining, upregulated XBP1 and GRP78/BiP splicing. Remarkably, the systemic toxicity and blood compatibility profile of PEG@mTa2O5 can greatly improve successive therapeutic outcomes of NMs while reducing their adverse side effects. Overall, our findings suggested that PEG@mTa2O5-induced endothelium apoptosis was partially mediated by the activation of the endoplasmic reticulum stress-mitochondrial cascade.
Collapse
Affiliation(s)
- Yuanyong Jiao
- Department of Vascular Surgery, The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Xiwei Zhang
- Department of Vascular Surgery, The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Hongyu Yang
- Department of Vascular Surgery, The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Hao Ma
- Department of Vascular Surgery, The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Junjie Zou
- Department of Vascular Surgery, The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China,CONTACT Junjie Zou Department of Vascular Surgery, The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Guangzhou Road 300, Gulou District, Nanjing210029, China
| |
Collapse
|
33
|
Lan Z, Zhao L, Peng L, Wan L, Liu D, Tang C, Chen G, Liu Y, Liu H. EIF2α/ATF4 pathway enhances proliferation of mesangial cell via cyclin D1 during endoplasmic reticulum stress in IgA nephropathy. Clin Immunol 2023; 257:109840. [PMID: 37939913 DOI: 10.1016/j.clim.2023.109840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 03/30/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023]
Abstract
IgA nephropathy (IgAN) is an essential cause of kidney failure and end-stage kidney disease worldwide. Mesangial hypercellularity is an important characteristic of IgAN, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress is a series of stress responses to restore the function of endoplasmic reticulum. We aimed to explore how ER stress functioned in kidneys of IgAN. We first examined ER stress in IgAN kidneys in vivo and in vitro, by testing the levels of ER stress associated proteins (BIP, p-eIF2α and ATF4). Our results showed that ER stress was activated in IgAN patients, mice and cell model. ER stress activation was related to the distribution of IgA deposition and the degree of mesangial proliferation. To determine the role of ER stress in mesangial cell (MC) proliferation of IgAN, we then tested the levels of ER stress and MC proliferation (cyclin D1, cell viability and cell cycle) through inhibiting ER stress associated proteins. After inhibiting ER stress associated proteins, ER stress was inactivated and cell proliferation was inhibited in MCs. We also explored the correlation between ER stress in the glomerulus and the clinical outcomes of IgAN patients in a prospective study. Patients with lower expression of p-eIF2α or ATF4 had higher rates of hematuria remission, proteinuria remission and clinical remission. In summary, our work outlines that in IgAN, ER stress mediated by eIF2α/ATF4 pathway promotes MC proliferation via up-regulating the expression of cyclin D1. Furthermore, p-eIF2α and ATF4 in the glomerulus negatively correlate with the clinical remission of IgAN patients.
Collapse
Affiliation(s)
- Zhixin Lan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lu Zhao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Liang Peng
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lili Wan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Di Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chengyuan Tang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Guochun Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yu Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
| | - Hong Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
| |
Collapse
|
34
|
Hecht JT, Veerisetty AC, Patra D, Hossain MG, Chiu F, Mobed C, Gannon FH, Posey KL. Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH). Biomolecules 2023; 13:1553. [PMID: 37892235 PMCID: PMC10605626 DOI: 10.3390/biom13101553] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/11/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.
Collapse
Affiliation(s)
- Jacqueline T. Hecht
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA; (J.T.H.); (A.C.V.); (M.G.H.); (F.C.)
| | - Alka C. Veerisetty
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA; (J.T.H.); (A.C.V.); (M.G.H.); (F.C.)
| | - Debabrata Patra
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Mohammad G. Hossain
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA; (J.T.H.); (A.C.V.); (M.G.H.); (F.C.)
| | - Frankie Chiu
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA; (J.T.H.); (A.C.V.); (M.G.H.); (F.C.)
| | - Claire Mobed
- Department of Biology, Rice University, Houston, TX 77005, USA;
| | - Francis H. Gannon
- Departments of Pathology and Immunology and Orthopedic Surgery, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Karen L. Posey
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA; (J.T.H.); (A.C.V.); (M.G.H.); (F.C.)
| |
Collapse
|
35
|
Akhter N, Wilson A, Arefanian H, Thomas R, Kochumon S, Al-Rashed F, Abu-Farha M, Al-Madhoun A, Al-Mulla F, Ahmad R, Sindhu S. Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α and MAPK/NF-κB Pathways. Int J Mol Sci 2023; 24:15186. [PMID: 37894865 PMCID: PMC10606873 DOI: 10.3390/ijms242015186] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Obesity and metabolic syndrome involve chronic low-grade inflammation called metabolic inflammation as well as metabolic derangements from increased endotoxin and free fatty acids. It is debated whether the endoplasmic reticulum (ER) stress in monocytic cells can contribute to amplify metabolic inflammation; if so, by which mechanism(s). To test this, metabolic stress was induced in THP-1 cells and primary human monocytes by treatments with lipopolysaccharide (LPS), palmitic acid (PA), or oleic acid (OA), in the presence or absence of the ER stressor thapsigargin (TG). Gene expression of tumor necrosis factor (TNF)-α and markers of ER/oxidative stress were determined by qRT-PCR, TNF-α protein by ELISA, reactive oxygen species (ROS) by DCFH-DA assay, hypoxia-inducible factor 1-alpha (HIF-1α), p38, extracellular signal-regulated kinase (ERK)-1,2, and nuclear factor kappa B (NF-κB) phosphorylation by immunoblotting, and insulin sensitivity by glucose-uptake assay. Regarding clinical analyses, adipose TNF-α was assessed using qRT-PCR/IHC and plasma TNF-α, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and oxidized low-density lipoprotein (OX-LDL) via ELISA. We found that the cooperative interaction between metabolic and ER stresses promoted TNF-α, ROS, CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF2) expression (p ≤ 0.0183),. However, glucose uptake was not impaired. TNF-α amplification was dependent on HIF-1α stabilization and p38 MAPK/p65 NF-κB phosphorylation, while the MAPK/NF-κB pathway inhibitors and antioxidants/ROS scavengers such as curcumin, allopurinol, and apocynin attenuated the TNF-α production (p ≤ 0.05). Individuals with obesity displayed increased adipose TNF-α gene/protein expression as well as elevated plasma levels of TNF-α, CRP, MDA, and OX-LDL (p ≤ 0.05). Our findings support a metabolic-ER stress cooperativity model, favoring inflammation by triggering TNF-α production via the ROS/CHOP/HIF-1α and MAPK/NF-κB dependent mechanisms. This study also highlights the therapeutic potential of antioxidants in inflammatory conditions involving metabolic/ER stresses.
Collapse
Affiliation(s)
- Nadeem Akhter
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Ajit Wilson
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Hossein Arefanian
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Reeby Thomas
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Shihab Kochumon
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Fatema Al-Rashed
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Mohamed Abu-Farha
- Department of Translational Research, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (M.A.-F.); (F.A.-M.)
| | - Ashraf Al-Madhoun
- Department of Genetics & Bioinformatics, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait;
- Animal & Imaging Core Facilities, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Department of Translational Research, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (M.A.-F.); (F.A.-M.)
| | - Rasheed Ahmad
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
| | - Sardar Sindhu
- Department of Immunology & Microbiology, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait; (N.A.); (A.W.); (H.A.); (R.T.); (S.K.); (F.A.-R.); (R.A.)
- Animal & Imaging Core Facilities, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait
| |
Collapse
|
36
|
Lampart A, Krowarsch D, Biadun M, Sorensen V, Szymczyk J, Sluzalska K, Wiedlocha A, Otlewski J, Zakrzewska M. Intracellular FGF1 protects cells from apoptosis through direct interaction with p53. Cell Mol Life Sci 2023; 80:311. [PMID: 37783936 PMCID: PMC10545594 DOI: 10.1007/s00018-023-04964-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 08/28/2023] [Accepted: 09/12/2023] [Indexed: 10/04/2023]
Abstract
Fibroblast growth factor 1 (FGF1) acts by activating specific tyrosine kinase receptors on the cell surface. In addition to this classical mode of action, FGF1 also exhibits intracellular activity. Recently, we found that FGF1 translocated into the cell interior exhibits anti-apoptotic activity independent of receptor activation and downstream signaling. Here, we show that expression of FGF1 increases the survival of cells treated with various apoptosis inducers, but only when wild-type p53 is present. The p53-negative cells were not protected by either ectopically expressed or translocated FGF1. We also confirmed the requirement of p53 for the anti-apoptotic intracellular activity of FGF1 by silencing p53, resulting in loss of the protective effect of FGF1. In contrast, in p53-negative cells, intracellular FGF1 regained its anti-apoptotic properties after transfection with wild-type p53. We also found that FGF1 directly interacts with p53 in cells and that the binding region is located in the DBD domain of p53. We therefore postulate that intracellular FGF1 protects cells from apoptosis by directly interacting with p53.
Collapse
Affiliation(s)
- Agata Lampart
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Daniel Krowarsch
- Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Martyna Biadun
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
- Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Vigdis Sorensen
- Advanced Light Microscopy Core Facility, Dept. Core Facilities, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway
| | - Jakub Szymczyk
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Katarzyna Sluzalska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Antoni Wiedlocha
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway
| | - Jacek Otlewski
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Malgorzata Zakrzewska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
| |
Collapse
|
37
|
Zhang X, Chen X, Qian F, Zhu Y, He G, Yang J, Wu X, Zhang H, Yu X, Liu X. Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer. Clin Transl Med 2023; 13:e1398. [PMID: 37700495 PMCID: PMC10497826 DOI: 10.1002/ctm2.1398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 07/20/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC), a heterogeneous subtype of breast cancer (BC), had poor prognosis. Endoplasmic reticulum (ER) stress was responsible for cellular processes and played a crucial role in the cell function. ER stress is a complex and dynamic process that can induce abnormal apoptosis and death. However, the underlying mechanism of ER stress involved in TNBC is not well defined. METHODS We identified ubiquitin-specific protease 19 (USP19) as a TNBC negative regulator for further investigation. The effects of USP19 on BC proliferation were assessed in vitro using proliferation test and cell-cycle assays, while the effects in vivo were examined using a mouse tumorigenicity model. Through in vitro flow cytometric analyses and in vivo TUNEL assays, cell apoptosis was assessed. Proteomics was used to examine the proteins that interact with USP19. RESULTS Multiple in vitro and in vivo tests showed that USP19 decreases TNBC cell growth while increasing apoptosis. Then, we demonstrated that USP19 interacts with deubiquitinates and subsequently stabilises family molecular chaperone regulator 6 (BAG6). BAG6 can boost B-cell lymphoma 2 (BCL2) ubiquitination and degradation, thereby raising ER calcium (Ca2+ ) levels and causing ER stress. We also found that the N6 -methyladenosine (m6 A) "writer" methyltransferase-like 14 (METTL14) increased global m6 A modification. CONCLUSIONS Our study reveals that USP19 elevates the intracellular Ca2+ concentration to alter ER stress via regulation of BAG6 and BCL2 stability and may be a viable therapeutic target for TNBC therapy.
Collapse
Affiliation(s)
- Xiaoqiang Zhang
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital)HangzhouChina
| | - Xuyu Chen
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Fangze Qian
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Yanhui Zhu
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Gao He
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Junzhe Yang
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Xian Wu
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Hongfei Zhang
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Xiafei Yu
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Xiaoan Liu
- Breast Disease CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| |
Collapse
|
38
|
Patel S, Pangarkar A, Mahajan S, Majumdar A. Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy. Metab Brain Dis 2023; 38:1841-1856. [PMID: 37289403 DOI: 10.1007/s11011-023-01239-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 05/19/2023] [Indexed: 06/09/2023]
Abstract
Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).
Collapse
Affiliation(s)
- Shivangi Patel
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India
| | - Arnika Pangarkar
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India
| | - Sakshi Mahajan
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India
| | - Anuradha Majumdar
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India.
| |
Collapse
|
39
|
García-Velázquez L, Massieu L. The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies. Front Mol Neurosci 2023; 16:1214092. [PMID: 37575967 PMCID: PMC10413579 DOI: 10.3389/fnmol.2023.1214092] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/07/2023] [Indexed: 08/15/2023] Open
Abstract
A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and diseases. Hence, KBs have been suggested as therapeutic tools for neurodegenerative diseases. KBs are an alternative fuel during fasting and starvation as they can be converted to Ac-CoA to produce ATP. A ketogenic diet (KD), enriched in fats and low in carbohydrates, induces KB production in the liver and favors their use in the brain. BHB is the most abundant KB in the circulation; in addition to its role as energy fuel, it exerts many actions that impact the set of proteins in the cell and tissue. BHB can covalently bind to proteins in lysine residues as a new post-translational modification (PTM) named β-hydroxybutyrylation (Kbhb). Kbhb has been identified in many proteins where Kbhb sites can be critical for binding to other proteins or cofactors. Kbhb is mostly found in proteins involved in chromatin structure, DNA repair, regulation of spliceosome, transcription, and oxidative phosphorylation. Histones are the most studied family of proteins with this PTM, and H3K9bhb is the best studied histone mark. Their target genes are mainly related to cell metabolism, chromatin remodeling and the control of circadian rhythms. The role of Kbhb on physiological processes is poorly known, but it might link KB metabolism to cell signaling and genome regulation. BHB also impacts the proteome by influencing proteostasis. This KB can modulate the Unfolded Protein Response (UPR) and autophagy, two processes involved in the maintenance of protein homeostasis through the clearance of accumulated unfolded and damaged proteins. BHB can support proteostasis and regulate the UPR to promote metabolism adaptation in the liver and prevent cell damage in the brain. Also, BHB stimulates autophagy aiding to the degradation of accumulated proteins. Protein aggregation is common to proteinopathies like Alzheimer's (AD) and Parkinson's (PD) diseases, where the KD and BHB treatment have shown favorable effects. In the present review, the current literature supporting the effects of KBs on proteome conformation and proteostasis is discussed, as well as its possible impact on AD and PD.
Collapse
Affiliation(s)
| | - Lourdes Massieu
- Department of Molecular Neuropathology, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), México City, Mexico
| |
Collapse
|
40
|
Song Y, Ma J, Fang L, Tang M, Gao X, Zhu D, Liu W. Endoplasmic reticulum stress-related gene model predicts prognosis and guides therapies in lung adenocarcinoma. BMC Bioinformatics 2023; 24:255. [PMID: 37328788 DOI: 10.1186/s12859-023-05384-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/13/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND The prognosis and survival of lung adenocarcinoma (LUAD) patients are still not promising despite recent breakthroughs in treatment. Endoplasmic reticulum stress (ERS) is a self-protective mechanism resulting from an imbalance in quality control of unfolded proteins when cells are stressed, which plays an active role in lung cancer development, but the relationship between ERS and the pathological characteristics and clinical prognosis of LUAD patients remains unclear. METHODS LASSO and Cox regression were applied based on sequencing information to construct the model, which was validated to be robust. The risk scores of the patients were calculated using the formula provided by the model, and the patients were divided into high and low-risk groups according to the median cut-off of risk scores. Cox regression analysis identifies independent prognostic factors for these patients, and enrichment analysis of prognosis-related genes was also performed. The relationship between risk scores and tumor mutation burden (TMB), cancer stem cell index, and drug sensitivity was explored. RESULTS We constructed a 13-gene prognostic model for LUAD patients. Patients in the high-risk group had worse overall survival, lower immune score and ESTIMATE score, higher TMB, higher cancer stem cell index, and higher sensitivity to conventional chemotherapeutic agents. In addition, we constructed a nomogram that predicts 5-year survival in LUAD patients, which helps clinicians to foresee the prognosis from a new perspective. CONCLUSIONS Our results highlight the association of ERS with LUAD and the potential use of ERS in guiding treatment.
Collapse
Affiliation(s)
- Yuqi Song
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Jianzun Ma
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Linan Fang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Xinliang Gao
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Dongshan Zhu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
| |
Collapse
|
41
|
ERTÜRK E, AKGÜN O, YILDIZ Y, ALPER KALKAN P, SALOMATINA OV, SALAKHUTDINOV NF, ULUKAYA E, ARI F. Soloxolone methyl induces apoptosis and oxidative/ER stress in breast cancer cells and target cancer stem cell population. Turk J Biol 2023; 47:247-261. [PMID: 38152618 PMCID: PMC10751089 DOI: 10.55730/1300-0152.2660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 08/31/2023] [Accepted: 06/05/2023] [Indexed: 12/29/2023] Open
Abstract
One of the most prevalent malignancies in women and one of the leading causes of cancer-related death is breast cancer. There is a need for new treatment approaches and drugs for breast cancer. Many studies show the high potential of triterpene compounds and their semisynthetic derivatives as anticancer agents due to their ability to induce apoptosis and suppress tumorigenesis. The effects of soloxolone methyl (SM), a semisynthetic derivative of 18-H-glycyrrhetinic acid, on the cytotoxicity and apoptosis of human breast cancer cell line (T-47D) and cancer stem cell (CSCs) population (mammospheres; CD44+/CD24-antigen) derived from breast cancer cells, were examined in this work. The ATP assay was used to determine SM growth-inhibitory effects. Fluorescent staining, caspase-cleaved cytokeratin 18, and flow cytometry analysis were used to determine the mode of the cell death. In addition, cell death was investigated at protein and gene levels by Western Blotting and PCR, respectively. SM resulted in cytotoxicity in a time and dose dependent manner via ROS production and ER stress in T-47D cells in 2 models. The mode of cell death was apoptosis, evidenced by phosphatidylserine exposure, caspase activation, and bax overexpression. In mammospheres as 3D model, SM decreased stem cell properties and induced cell death. Taken together, SM may be a promising agent in the treatment of breast cancer, especially due to its antigrowth activity on CSCs.
Collapse
Affiliation(s)
- Elif ERTÜRK
- Vocational School of Health Services, Bursa Uludağ University, Bursa,
Turkiye
| | - Oğuzhan AKGÜN
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
| | - Yaren YILDIZ
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
| | - Pınar ALPER KALKAN
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
- Aziz Sancar Experimental Medicine Research Institute, Molecular Medicine, İstanbul University, İstanbul,
Turkiye
| | - Oksana V. SALOMATINA
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk,
Russia
| | - Nariman F. SALAKHUTDINOV
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk,
Russia
| | - Engin ULUKAYA
- Department of Clinical Biochemistry, Faculty of Medicine, İstinye University, İstanbul,
Turkiye
| | - Ferda ARI
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
| |
Collapse
|
42
|
Waigi EW, Webb RC, Moss MA, Uline MJ, McCarthy CG, Wenceslau CF. Soluble and insoluble protein aggregates, endoplasmic reticulum stress, and vascular dysfunction in Alzheimer's disease and cardiovascular diseases. GeroScience 2023; 45:1411-1438. [PMID: 36823398 PMCID: PMC10400528 DOI: 10.1007/s11357-023-00748-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 01/28/2023] [Indexed: 02/25/2023] Open
Abstract
Dementia refers to a particular group of symptoms characterized by difficulties with memory, language, problem-solving, and other thinking skills that affect a person's ability to perform everyday activities. Alzheimer's disease (AD) is the most common form of dementia, affecting about 6.2 million Americans aged 65 years and older. Likewise, cardiovascular diseases (CVDs) are a major cause of disability and premature death, impacting 126.9 million adults in the USA, a number that increases with age. Consequently, CVDs and cardiovascular risk factors are associated with an increased risk of AD and cognitive impairment. They share important age-related cardiometabolic and lifestyle risk factors, that make them among the leading causes of death. Additionally, there are several premises and hypotheses about the mechanisms underlying the association between AD and CVD. Although AD and CVD may be considered deleterious to health, the study of their combination constitutes a clinical challenge, and investigations to understand the mechanistic pathways for the cause-effect and/or shared pathology between these two disease constellations remains an active area of research. AD pathology is propagated by the amyloid β (Aβ) peptides. These peptides give rise to small, toxic, and soluble Aβ oligomers (SPOs) that are nonfibrillar, and it is their levels that show a robust correlation with the extent of cognitive impairment. This review will elucidate the interplay between the effects of accumulating SPOs in AD and CVDs, the resulting ER stress response, and their role in vascular dysfunction. We will also address the potential underlying mechanisms, including the possibility that SPOs are among the causes of vascular injury in CVD associated with cognitive decline. By revealing common mechanistic underpinnings of AD and CVD, we hope that novel experimental therapeutics can be designed to reduce the burden of these devastating diseases. Graphical abstract Alzheimer's disease (AD) pathology leads to the release of Aβ peptides, and their accumulation in the peripheral organs has varying effects on various components of the cardiovascular system including endoplasmic reticulum (ER) stress and vascular damage. Image created with BioRender.com.
Collapse
Affiliation(s)
- Emily W Waigi
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - R Clinton Webb
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
| | - Melissa A Moss
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, USA
| | - Mark J Uline
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, USA
| | - Cameron G McCarthy
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
| | - Camilla Ferreira Wenceslau
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA.
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA.
| |
Collapse
|
43
|
Wang P, Liu X, Chen Y, Jun-Hao ET, Yao Z, Min-Wen JC, Yan-Jiang BC, Ma S, Ma W, Luo L, Guo L, Song D, Shyh-Chang N. Adult progenitor rejuvenation with embryonic factors. Cell Prolif 2023; 56:e13459. [PMID: 37177849 DOI: 10.1111/cpr.13459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 05/15/2023] Open
Abstract
During ageing, adult stem cells' regenerative properties decline, as they undergo replicative senescence and lose both their proliferative and differentiation capacities. In contrast, embryonic and foetal progenitors typically possess heightened proliferative capacities and manifest a more robust regenerative response upon injury and transplantation, despite undergoing many rounds of mitosis. How embryonic and foetal progenitors delay senescence and maintain their proliferative and differentiation capacities after numerous rounds of mitosis, remains unknown. It is also unclear if defined embryonic factors can rejuvenate adult progenitors to confer extended proliferative and differentiation capacities, without reprogramming their lineage-specific fates or inducing oncogenic transformation. Here, we report that a minimal combination of LIN28A, TERT, and sh-p53 (LTS), all of which are tightly regulated and play important roles during embryonic development, can delay senescence in adult muscle progenitors. LTS muscle progenitors showed an extended proliferative capacity, maintained a normal karyotype, underwent myogenesis normally, and did not manifest tumorigenesis nor aberrations in lineage differentiation, even in late passages. LTS treatment promoted self-renewal and rescued the pro-senescence phenotype of aged cachexia patients' muscle progenitors, and promoted their engraftment for skeletal muscle regeneration in vivo. When we examined the mechanistic basis for LIN28A's role in the LTS minimum combo, let-7 microRNA suppression could not fully explain how LIN28A promoted muscle progenitor self-renewal. Instead, LIN28A was promoting the translation of oxidative phosphorylation mRNAs in adult muscle progenitors to optimize mitochondrial reactive oxygen species (mtROS) and mitohormetic signalling. Optimized mtROS induced a variety of mitohormetic stress responses, including the hypoxic response for metabolic damage, the unfolded protein response for protein damage, and the p53 response for DNA damage. Perturbation of mtROS levels specifically abrogated the LIN28A-driven hypoxic response in Hypoxia Inducible Factor-1α (HIF1α) and glycolysis, and thus LTS progenitor self-renewal, without affecting normal or TS progenitors. Our findings connect embryonically regulated factors to mitohormesis and progenitor rejuvenation, with implications for ageing-related muscle degeneration.
Collapse
Affiliation(s)
- Peng Wang
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xupeng Liu
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu Chen
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Elwin Tan Jun-Hao
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Ziyue Yao
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jason Chua Min-Wen
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Benjamin Chua Yan-Jiang
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Shilin Ma
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Wenwu Ma
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lanfang Luo
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Luyao Guo
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Dan Song
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ng Shyh-Chang
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
44
|
Guan Y, Chang G, Zhao J, Wang Q, Qin J, Tang M, Wang S, Ma L, Ma J, Sun G, Zhou Y, Huang J. Parallel evolution of two AIM24 protein subfamilies and their conserved functions in ER stress tolerance in land plants. PLANT COMMUNICATIONS 2023; 4:100513. [PMID: 36578211 DOI: 10.1016/j.xplc.2022.100513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/25/2022] [Accepted: 12/23/2022] [Indexed: 05/11/2023]
Abstract
Despite decades of efforts in genome sequencing and functional characterization, some important protein families remain poorly understood. In this study, we report the classification, evolution, and functions of the largely uncharacterized AIM24 protein family in plants, including the identification of a novel subfamily. We show that two AIM24 subfamilies (AIM24-A and AIM24-B) are commonly distributed in major plant groups. These two subfamilies not only have modest sequence similarities and different gene structures but also are of independent bacterial ancestry. We performed comparative functional investigations on the two AIM24 subfamilies using three model plants: the moss Physcomitrium patens, the liverwort Marchantia polymorpha, and the flowering plant Arabidopsis thaliana. Intriguingly, despite their significant differences in sequence and gene structure, both AIM24 subfamilies are involved in ER stress tolerance and the unfolded protein response (UPR). In addition, transformation of the AIM24-A gene from P. patens into the AIM24-B null mutant of A. thaliana could at least partially rescue ER stress tolerance and the UPR. We also discuss the role of AIM24 genes in plant development and other cellular activities. This study provides a unique example of parallel evolution in molecular functions and can serve as a foundation for further investigation of the AIM24 family in plants.
Collapse
Affiliation(s)
- Yanlong Guan
- Key Laboratory for Plant Diversity and Biogeography of East Asia, Yunnan Key Laboratory for Fungal Diversity and Green Development, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Guanxiao Chang
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jinjie Zhao
- Key Laboratory for Plant Diversity and Biogeography of East Asia, Yunnan Key Laboratory for Fungal Diversity and Green Development, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Qia Wang
- Key Laboratory for Plant Diversity and Biogeography of East Asia, Yunnan Key Laboratory for Fungal Diversity and Green Development, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Jiali Qin
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Mengmeng Tang
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Shuanghua Wang
- Key Laboratory for Plant Diversity and Biogeography of East Asia, Yunnan Key Laboratory for Fungal Diversity and Green Development, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Lan Ma
- Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Jianchao Ma
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Guiling Sun
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Yun Zhou
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jinling Huang
- Key Laboratory for Plant Diversity and Biogeography of East Asia, Yunnan Key Laboratory for Fungal Diversity and Green Development, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng 475004, China; Department of Biology, East Carolina University, Greenville, NC 27858, USA.
| |
Collapse
|
45
|
Feng C, Jin C, Liu K, Yang Z. Microbiota-derived short chain fatty acids: Their role and mechanisms in viral infections. Biomed Pharmacother 2023. [DOI: 10.1016/j.biopha.2023.114414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023] Open
|
46
|
Raines LN, Huang SCC. How the Unfolded Protein Response Is a Boon for Tumors and a Bane for the Immune System. Immunohorizons 2023; 7:256-264. [PMID: 37067519 PMCID: PMC10579845 DOI: 10.4049/immunohorizons.2200064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 03/28/2023] [Indexed: 04/18/2023] Open
Abstract
The correct folding of proteins is essential for appropriate cell function and is tightly regulated within the endoplasmic reticulum (ER). Environmental challenges and cellular conditions disrupt ER homeostasis and induce ER stress, which adversely affect protein folding and activate the unfolded protein response (UPR). It is now becoming recognized that cancer cells can overcome survival challenges posed within the tumor microenvironment by activating the UPR. Furthermore, the UPR has also been found to impose detrimental effects on immune cells by inducing immunoinhibitory activity in both tumor-infiltrating innate and adaptive immune cells. This suggests that these signaling axes may be important therapeutic targets, resulting in multifaceted approaches to eradicating tumor cells. In this mini-review, we discuss the role of the UPR in driving tumor progression and modulating the immune system's ability to target cancer cells. Additionally, we highlight some of the key unanswered questions that may steer future UPR research.
Collapse
Affiliation(s)
- Lydia N. Raines
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Stanley Ching-Cheng Huang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
| |
Collapse
|
47
|
Padarath K, Deroubaix A, Kramvis A. The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma. Viruses 2023; 15:v15040857. [PMID: 37112837 PMCID: PMC10144019 DOI: 10.3390/v15040857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer.
Collapse
|
48
|
Hecht JT, Chiu F, Veerisetty A, Hossain M, Posey KL. Matrix in Medicine: Health Consequences of Mutant Cartilage Oligomeric Matrix Protein and its relationship to abnormal growth and to joint degeneration. Matrix Biol 2023; 119:101-111. [PMID: 37001593 DOI: 10.1016/j.matbio.2023.03.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 03/10/2023] [Accepted: 03/24/2023] [Indexed: 04/01/2023]
Abstract
Cartilage oligomeric matrix protein (COMP), an extracellular matrix protein, has been shown to enhance proliferation and mechanical integrity in the matrix, supporting functions of the growth plate and articular cartilage. Mutations in COMP cause pseudoachondroplasia (PSACH), a severe dwarfing condition associated with premature joint degeneration and significant lifelong joint pain. The MT (mutant)-COMP mouse mimics PSACH with decreased limb growth, early joint degeneration and pain. Ablation of endoplasmic reticulum stress CHOP signaling eliminated pain and prevented joint degeneration. The health effects of mutant COMP are discussed in relation to cellular/chondrocyte stress in the growth plate, articular cartilage and nearby tissues, and the implications for therapeutic approaches. There are many similarities between osteoarthritis and mutant-COMP protein-induced joint degeneration, suggesting that the relevance of findings in the joints may extend beyond PSACH to idiopathic primary OA.
Collapse
|
49
|
Li J, Ge H, Xu Y, Xie J, Karim N, Yan F, Mo J, Chen W. Chlorogenic acid alleviates oxidative damage in hepatocytes by regulating miR-199a-5p/GRP78 axis. FOOD BIOSCI 2023. [DOI: 10.1016/j.fbio.2023.102595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
|
50
|
Yan K, Zheng J, Kluth MA, Li L, Ganss C, Yard B, Magdeburg R, Frank MH, Pallavi P, Keese M. ABCB5 + mesenchymal stromal cells therapy protects from hypoxia by restoring Ca 2+ homeostasis in vitro and in vivo. Stem Cell Res Ther 2023; 14:24. [PMID: 36759868 PMCID: PMC9912525 DOI: 10.1186/s13287-022-03228-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Hypoxia in ischemic disease impairs Ca2+ homeostasis and may promote angiogenesis. The therapeutic efficacy of mesenchymal stromal cells (MSCs) in peripheral arterial occlusive disease is well established, yet its influence on cellular Ca2+ homeostasis remains to be elucidated. We addressed the influence of ATP-binding cassette subfamily B member 5 positive mesenchymal stromal cells (ABCB5+ MSCs) on Ca2+ homeostasis in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. METHODS Hypoxia was induced in HUVECs by Cobalt (II) chloride (CoCl2) or Deferoxamine (DFO). Dynamic changes in the cytosolic- and endoplasmic reticulum (ER) Ca2+ and changes in reactive oxygen species were assessed by appropriate fluorescence-based sensors. Metabolic activity, cell migration, and tube formation were assessed by standard assays. Acute-on-chronic ischemia in Apolipoprotein E knock-out (ApoE-/-) mice was performed by double ligation of the right femoral artery (DFLA). ABCB5+ MSC cells were injected into the ischemic limb. Functional recovery after DFLA and histology of gastrocnemius and aorta were assessed. RESULTS Hypoxia-induced impairment of cytosolic and ER Ca2+ were restored by ABCB5+ MSCs or their conditioned medium. Similar was found for changes in intracellular ROS production, metabolic activity, migratory ability and tube formation. The restoration was paralleled by an increased expression of the Ca2+ transporter Sarco-/endoplasmic reticulum ATPase 2a (SERCA2a) and the phosphorylation of Phospholamban (PLN). In acute-on-chronic ischemia, ABCB5+ MSCs treated mice showed a higher microvascular density, increased SERCA2a expression and PLN phosphorylation relative to untreated controls. CONCLUSIONS ABCB5+ MSCs therapy can restore cellular Ca2+ homeostasis, which may beneficially affect the angiogenic function of endothelial cells under hypoxia in vitro and in vivo.
Collapse
Affiliation(s)
- Kaixuan Yan
- grid.7700.00000 0001 2190 4373Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jiaxing Zheng
- grid.7700.00000 0001 2190 4373Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | | | - Lin Li
- grid.7700.00000 0001 2190 4373Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Ganss
- TICEBA GmbH, Heidelberg, Germany ,grid.476673.7RHEACELL GmbH & Co. KG, Heidelberg, Germany
| | - Benito Yard
- grid.7700.00000 0001 2190 4373V Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Richard Magdeburg
- grid.411778.c0000 0001 2162 1728Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161 Mannheim, Germany
| | - Markus H. Frank
- grid.38142.3c000000041936754XDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA ,grid.38142.3c000000041936754XTransplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA USA ,grid.38142.3c000000041936754XHarvard Stem Cell Institute, Harvard University, Cambridge, MA USA ,grid.1038.a0000 0004 0389 4302School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Prama Pallavi
- Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany.
| | - Michael Keese
- Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,Department for General and Visceral Surgery, Theresienkrankenhaus Mannheim, Mannheim, Germany. .,Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany.
| |
Collapse
|