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Alotaibi G, Alkhammash A. Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases. Eur J Pharmacol 2025; 998:177509. [PMID: 40089262 DOI: 10.1016/j.ejphar.2025.177509] [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: 11/02/2024] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/17/2025]
Abstract
The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.
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Affiliation(s)
- Ghallab Alotaibi
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia.
| | - Abdullah Alkhammash
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia.
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2
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Thompson AD, Victor Santiago Raj P, Scholpa NE, Schnellmann RG. Repurposing mitochondria-targeted therapeutics for kidney diseases. Kidney Int 2025; 107:617-627. [PMID: 39855593 PMCID: PMC12013279 DOI: 10.1016/j.kint.2024.12.020] [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: 06/20/2024] [Revised: 10/29/2024] [Accepted: 12/09/2024] [Indexed: 01/27/2025]
Abstract
The kidney is one of the most metabolically demanding organs in the human body and requires a large amount of energy, in the form of adenosine triphosphate (ATP), to perform and maintain normal kidney functions. To meet this energy demand, proximal tubule cells within the nephron segments of the renal cortex are mitochondrially dense with high oxygen consumption rates. Mitochondria are complex organelles involved in diverse cellular and molecular functions, including the production of ATP, calcium homeostasis, and phospholipid regulation. Mitochondrial dysfunction is critical in the onset and progression of kidney disease. Dysfunctional renal mitochondria have been linked with alterations in redox homeostasis, impaired bioenergetics, oxidative stress, and inflammation, all of which result in renal cell injury and death, as well as fibrotic accumulation in kidney injury and disease. As such, interest in the development and/or repurposing of mitochondria-targeted therapeutics for the potential treatment of kidney diseases has recently surged. Although novel therapeutics and promising new drug targets have been identified, drug repurposing for kidney diseases offers numerous advantages over traditional drug discovery initiatives, including reduced cost, time of therapeutic development, and preclinical testing, in addition to known pharmacokinetics/pharmacodynamics and safety profiles. Here, we provide an overview of mitochondrial dysfunction in the context of kidney injury and disease and shed light on promising mitochondria-targeted therapeutic agents that display repurposing potential for the restoration of kidney function and/or acceleration of renal recovery.
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Affiliation(s)
- Austin D Thompson
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA; Southern Arizona VA Health Care System, Tucson, Arizona, USA; Southwest Environmental Health Science Center, University of Arizona, Tucson, Arizona, USA
| | - Paul Victor Santiago Raj
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA
| | - Natalie E Scholpa
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA; Southern Arizona VA Health Care System, Tucson, Arizona, USA
| | - Rick G Schnellmann
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA; Southern Arizona VA Health Care System, Tucson, Arizona, USA; Southwest Environmental Health Science Center, University of Arizona, Tucson, Arizona, USA.
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3
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Santiago Raj PV, Scholpa NE, Hurtado KA, Janda J, Hortareas J, Schnellmann RG. 5-Hydroxytryptamine 1F Receptor Agonist Lasmiditan Differentially Regulates Successful Repair and Failed Repair Genes in a Mouse Model of Acute Kidney Injury. ACS Pharmacol Transl Sci 2024; 7:3045-3055. [PMID: 39416968 PMCID: PMC11475317 DOI: 10.1021/acsptsci.4c00246] [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: 04/26/2024] [Revised: 08/28/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024]
Abstract
Increasing evidence substantiates the role of mitochondrial dysfunction, inflammation, fibrosis, and cell senescence in the onset and progression of acute kidney injury (AKI) to chronic kidney disease . The underlying governing cellular and transcriptional events, however, are not fully understood. Recently, the key factors that regulate successful and failed repair states in the proximal tubule have been identified at a single-cell resolution following bilateral ischemia-reperfusion (I/R) in a mouse model of AKI. Previously, our group showed that treatment with the FDA-approved selective 5-hydroxytryptamine receptor 1F agonist lasmiditan following AKI induces mitochondrial biogenesis , restores renal mitochondrial function, and increases renal and vascular recovery in vivo. Here, we assessed the effect of lasmiditan on transcriptional and translational changes that are responsible for successful repair, injury, and failed repair states in the renal cortex following I/R-induced AKI. Increased levels of successful repair genes such as acyl-coA synthase medium-chain family member 2a, low-density lipoprotein receptor-related protein 2, solute carrier family 5 member 12, and hepatocyte nuclear factor 4 alpha were observed with 6 and 12 days of lasmiditan treatment following AKI compared to vehicle control. While 6 days of lasmiditan treatment had no effect on failed repair genes, the administration of lasmiditan for 12 days decreased the levels of vascular cell adhesion protein 1, tumor necrosis factor α, and interleukin-1β, which drive maladaptive repair. These data reveal that lasmiditan treatment post-AKI differentially regulates successful and failed repair gene expression in the renal cortex, likely contributing to the restoration of renal function and providing a potential targeted therapeutic pathway for the treatment of AKI.
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Affiliation(s)
- Paul Victor Santiago Raj
- Department
of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85719, United States
| | - Natalie E. Scholpa
- Department
of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85719, United States
- Southern
Arizona VA Health Care System, Tucson, Arizona 85723-0002, United States
| | - Kevin A. Hurtado
- Department
of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85719, United States
- Southwest
Environmental Health Science Center, University
of Arizona, Tucson, Arizona 85721, United States
| | - Jaroslav Janda
- Department
of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85719, United States
| | - John Hortareas
- Southern
Arizona VA Health Care System, Tucson, Arizona 85723-0002, United States
| | - Rick G. Schnellmann
- Department
of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85719, United States
- Southern
Arizona VA Health Care System, Tucson, Arizona 85723-0002, United States
- Southwest
Environmental Health Science Center, University
of Arizona, Tucson, Arizona 85721, United States
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Efiong EE, Bazireh H, Fuchs M, Amadi PU, Effa E, Sharma S, Schmaderer C. Crosstalk of Hyperglycaemia and Cellular Mechanisms in the Pathogenesis of Diabetic Kidney Disease. Int J Mol Sci 2024; 25:10882. [PMID: 39456664 PMCID: PMC11507194 DOI: 10.3390/ijms252010882] [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: 08/27/2024] [Revised: 09/27/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024] Open
Abstract
Among all nephropathies, diabetic kidney disease (DKD) is the most common cause of kidney impairment advancement to end-stage renal disease (ESRD). Although DKD has no cure, the disease is commonly managed by strict control of blood glucose and blood pressure, and in most of these cases, kidney function often deteriorates, resulting in dialysis, kidney replacement therapy, and high mortality. The difficulties in finding a cure for DKD are mainly due to a poor understanding of the underpinning complex cellular mechanisms that could be identified as druggable targets for the treatment of this disease. The review is thus aimed at giving insight into the interconnection between chronic hyperglycaemia and cellular mechanistic perturbations of nephropathy in diabetes. A comprehensive literature review of observational studies on DKD published within the past ten years, with 57 percent published within the past three years was carried out. The article search focused on original research studies and reviews published in English. The articles were explored using Google Scholar, Medline, Web of Science, and PubMed databases based on keywords, titles, and abstracts related to the topic. This article provides a detailed relationship between hyperglycaemia, oxidative stress, and various cellular mechanisms that underlie the onset and progression of the disease. Moreover, it also shows how these mechanisms affect organelle dysfunction, resulting in fibrosis and podocyte impairment. The advances in understanding the complexity of DKD mechanisms discussed in this review will expedite opportunities to develop new interventions for treating the disease.
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Affiliation(s)
- Esienanwan Esien Efiong
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Department of Biochemistry, Faculty of Science, Federal University of Lafia, PMB 146, Lafia 950101, Nigeria
| | - Homa Bazireh
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Faculty of Medicine, Ludwig-Maximilians-University München, 81377 München, Germany
| | - Markéta Fuchs
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Peter Uchenna Amadi
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Department of Biochemistry, Imo State University, Owerri 460222, Nigeria
| | - Emmanuel Effa
- Division of Nephrology, Department of Internal Medicine, Faculty of Clinical Sciences, University of Calabar, PMB 1115, Calabar 540271, Nigeria
| | - Sapna Sharma
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- German Research Center for Environmental Health, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Christoph Schmaderer
- Abteilung für Nephrologie, Klinikum Rechts der Isar, der Technischen Universität München, 81675 München, Germany
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Kusaczuk M, Tovar-Ambel E, Martín-Cabrera P, Lorente M, Salvador-Tormo N, Mikłosz A, Chabowski A, Velasco G, Naumowicz M. Cytotoxicity, Proapoptotic Activity and Drug-like Potential of Quercetin and Kaempferol in Glioblastoma Cells: Preclinical Insights. Int J Mol Sci 2024; 25:10740. [PMID: 39409069 PMCID: PMC11477293 DOI: 10.3390/ijms251910740] [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: 09/05/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Despite the increasing understanding of the pathogenesis of glioblastoma (GBM), treatment options for this tumor remain limited. Recently, the therapeutic potential of natural compounds has attracted great interest. Thus, dietary flavonoids quercetin (QCT) and kaempferol (KMF) were investigated as potential cytostatic agents in GBM. Moreover, the physicochemical properties of QCT and KMF, determining their bioavailability and therapeutic efficiency, were evaluated. We proved that both polyphenols significantly reduced the viability of GBM cells. We also demonstrated that both QCT and KMF evoked the cytotoxic effect in T98G cells via induction of apoptotic cell death as shown by increased activity of caspase 3/7 and caspase 9 together with an overexpression of the cleaved form of PARP. Apoptosis was additionally accompanied by the activation of stress responses in QCT- and KMF-treated cells. Both polyphenols caused oxidative stress and endoplasmic reticulum (ER) stress, as demonstrated by the increased generation of reactive oxygen species (ROS), deregulated expressions of superoxide dismutases (SOD2 and Sod1 on protein and transcriptomic levels, respectively), as well as an overexpression of ERO1α, GRP78, p-JNK, and an up-regulation of Chop, Atf4 and Atf6α genes. The antitumor effect of QCT and KMF was also confirmed in vivo, showing reduced growth of tumor xenografts in the chick chorioallantoic membrane (CAM) experiment. Moreover, electrophoretic light scattering (ELS) was used to measure the zeta potential of cell membranes upon exposition to QCT and KMF. Additionally, on the basis of existing physicochemical data, the drug-likeness score of QCT and KMF was evaluated. Analyses showed that both compounds accomplish Lipinski's Rule of 5, and they both fit into the criteria of good central nervous system (CNS) drugs. Altogether, our data support the idea that QCT and KMF might be plausible candidates for evaluation as therapeutic agents in preclinical models of glioblastoma.
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Affiliation(s)
- Magdalena Kusaczuk
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland
| | - Elena Tovar-Ambel
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University and Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain; (E.T.-A.); (P.M.-C.); (M.L.); (N.S.-T.); (G.V.)
| | - Paola Martín-Cabrera
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University and Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain; (E.T.-A.); (P.M.-C.); (M.L.); (N.S.-T.); (G.V.)
| | - Mar Lorente
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University and Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain; (E.T.-A.); (P.M.-C.); (M.L.); (N.S.-T.); (G.V.)
| | - Nélida Salvador-Tormo
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University and Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain; (E.T.-A.); (P.M.-C.); (M.L.); (N.S.-T.); (G.V.)
| | - Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (A.M.); (A.C.)
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (A.M.); (A.C.)
| | - Guillermo Velasco
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University and Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain; (E.T.-A.); (P.M.-C.); (M.L.); (N.S.-T.); (G.V.)
| | - Monika Naumowicz
- Department of Physical Chemistry, Faculty of Chemistry, University of Bialystok, K. Ciolkowskiego 1K, 15-245 Bialystok, Poland
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Prasad MK, Victor PS, Ganesh GV, Juttada U, Kumpatla S, Viswanathan V, Ramkumar KM. Sodium-Glucose Cotransporter-2 Inhibitor Suppresses Endoplasmic Reticulum Stress and Oxidative Stress in Diabetic Nephropathy Through Nrf2 Signaling: A Clinical and Experimental Study. J Clin Pharmacol 2024; 64:1193-1203. [PMID: 38831713 DOI: 10.1002/jcph.2465] [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: 03/17/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024]
Abstract
Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium-glucose co-transporter-2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP-1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow-up of 6 months. Additionally, THP-1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF-α and IFN-γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM-treated THP-1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM-treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression.
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Affiliation(s)
- Murali Krishna Prasad
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Paul S Victor
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Goutham V Ganesh
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Udayama Juttada
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Satyavani Kumpatla
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Vijay Viswanathan
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
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Lin WC, Hoe BC, Li X, Lian D, Zeng X. Glucose Metabolism-Modifying Natural Materials for Potential Feed Additive Development. Pharmaceutics 2024; 16:1208. [PMID: 39339244 PMCID: PMC11435105 DOI: 10.3390/pharmaceutics16091208] [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: 07/19/2024] [Revised: 08/20/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Glucose, a primary energy source derived from animals' feed ration, is crucial for their growth, production performance, and health. However, challenges such as metabolic stress, oxidative stress, inflammation, and gut microbiota disruption during animal production practices can potentially impair animal glucose metabolism pathways. Phytochemicals, probiotics, prebiotics, and trace minerals are known to change the molecular pathway of insulin-dependent glucose metabolism and improve glucose uptake in rodent and cell models. These compounds, commonly used as animal feed additives, have been well studied for their ability to promote various aspects of growth and health. However, their specific effects on glucose uptake modulation have not been thoroughly explored. This article focuses on glucose metabolism is on discovering alternative non-pharmacological treatments for diabetes in humans, which could have significant implications for developing feed additives that enhance animal performance by promoting insulin-dependent glucose metabolism. This article also aims to provide information about natural materials that impact glucose uptake and to explore their potential use as non-antibiotic feed additives to promote animal health and production. Further exploration of this topic and the materials involved could provide a basis for new product development and innovation in animal nutrition.
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Affiliation(s)
- Wei-Chih Lin
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
- Kemin (China) Technologies Co., Ltd., Zhuhai 519040, China
| | - Boon-Chin Hoe
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
- Kemin (China) Technologies Co., Ltd., Zhuhai 519040, China
| | - Xianming Li
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China
| | - Daizheng Lian
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China
| | - Xiaowei Zeng
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
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Suwannalert P, Panpinyaporn P, Wantanachaisaeng P, Teeppaibul T, Worawichitchaikun T, Koomsang T, Naktubtim C, Payuhakrit W. 17-AAG Induces Endoplasmic Reticulum Stress-mediated Apoptosis in Breast Cancer Cells, Possibly Through PERK/eIF2α Up-regulation. In Vivo 2024; 38:2228-2238. [PMID: 39187325 PMCID: PMC11363749 DOI: 10.21873/invivo.13687] [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: 04/20/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND/AIM Breast cancer is the most predominant type of cancer affecting women worldwide and the current therapeutic treatment for breast cancer patients is not adequately effective. This study aimed to investigate the mechanism of 17-AAG, a heat shock protein (HSP90) inhibitor, as a treatment for inducing breast cancer cell apoptosis. MATERIALS AND METHODS The pharmacology network was employed to examine the correlation of 17-AAG with the gene expression profiles of breast cancer, obtained by Gene Expression Profiling Interactive Analysis (GEPIA). MTT and flow cytometry were utilized to investigate cell proliferation and cell apoptosis, respectively. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay and western blot analysis were employed to examine the correlation between cellular oxidant levels and protein expression. Immunofluorescence staining was utilized to confirm the protein localization and assess DNA damage. RESULTS The pharmacological network analysis revealed that HSP90 serves as the common target connecting 17-AAG and breast cancer genes. Treatment with 17-AAG significantly increased cell apoptosis. Moreover, the treatment resulted in up-regulation of cellular oxidant levels and PERK/eIF2α expression. In line with these, protein localization after treatment revealed an increase in DNA damage, correlating with higher ER stress levels. Furthermore, GEPIA demonstrated that PERK and eIF2α expression were significantly higher in breast invasive carcinoma compared to other tumor types. CONCLUSION HSP90 emerges as a potential target for inducing apoptosis in breast cancer cells by disrupting protein homeostasis in the endoplasmic reticulum, possibly through PERK/eIF2α up-regulation. 17-AAG, an HSP90 inhibitor, may therefore potentially hold an alternative therapeutic strategy for breast cancer treatment.
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Affiliation(s)
- Prasit Suwannalert
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | | | - Teerapat Teeppaibul
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | - Thidarat Koomsang
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Chonnapat Naktubtim
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Witchuda Payuhakrit
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
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9
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Zeng X, Zhang Y, Tian L, Zheng Y, Zhang J, Wu Z. Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy. Biochem Biophys Res Commun 2024; 721:149972. [PMID: 38772213 DOI: 10.1016/j.bbrc.2024.149972] [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: 02/13/2024] [Revised: 04/02/2024] [Accepted: 04/18/2024] [Indexed: 05/23/2024]
Abstract
Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in reactive oxygen species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.
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Affiliation(s)
- Xiaojiao Zeng
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Yuanyuan Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Ling Tian
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Yin Zheng
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021 China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong, 250012, China
| | - Jingyun Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China.
| | - Zhongming Wu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021 China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong, 250012, China.
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10
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Ye K, Zhao Y, Huang W, Zhu Y. Sodium butyrate improves renal injury in diabetic nephropathy through AMPK/SIRT1/PGC-1α signaling pathway. Sci Rep 2024; 14:17867. [PMID: 39090182 PMCID: PMC11294604 DOI: 10.1038/s41598-024-68227-8] [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: 01/18/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024] Open
Abstract
Diabetic nephropathy (DN) is a prototypical chronic energy metabolism imbalance disease. The AMPK/Sirt1/PGC-1α signaling pathway plays a pivotal role in regulating energy metabolism throughout the body. Gut microbiota ferment indigestible carbohydrates to produce a variety of metabolites, particularly short-chain fatty acids (SCFAs), which exert positive effects on energy metabolism. However, the potential for SCFAs to ameliorate DN-associated renal injury via the AMPK/Sirt1/PGC-1α pathway remains a matter of debate. In this study, we investigated the effects of sodium butyrate (NaB), a SCFA, on energy metabolism in mice with spontaneous DN at two different doses. Body weight, blood glucose and lipid levels, urinary protein excretion, liver and kidney function, interleukin-6 (IL-6) levels, and the expressions of AMPK, phosphorylated AMPK (p-AMPK), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), and glucagon-like peptide-1 receptor (GLP-1R) were monitored in mice. Additionally, butyrate levels, gut microbiota composition, and diversity in colonic stool were also assessed. Our findings demonstrate that exogenous NaB supplementation can improve hyperglycemia and albuminuria, reduce renal tissue inflammation, inhibit extracellular matrix accumulation and glomerular hypertrophy, and could alter the gut microbiota composition in DN. Furthermore, NaB was found to upregulate the expressions of MFN2, OPA1, p-AMPK, and GLP-1R in DN renal tissue. These results suggest that NaB could improve the composition of gut microbiota in DN, activate the AMPK/Sirt1/PGC-1α signaling pathway, and enhance mitochondrial function to regulate energy metabolism throughout the body. Collectively, our findings indicate that NaB may be a novel therapeutic agent for the treatment of DN.
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Affiliation(s)
- Kaili Ye
- Department of Hematology of Wenzhou People's Hospital, The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, No. 299, Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, China
| | - Yanling Zhao
- Department of Nephrology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Wen Huang
- Department of Nephrology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yonglin Zhu
- Department of Hematology of Wenzhou People's Hospital, The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, No. 299, Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, China.
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11
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Zhang Y, Guo S, Fu X, Zhang Q, Wang H. Emerging insights into the role of NLRP3 inflammasome and endoplasmic reticulum stress in renal diseases. Int Immunopharmacol 2024; 136:112342. [PMID: 38820956 DOI: 10.1016/j.intimp.2024.112342] [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: 03/17/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 06/02/2024]
Abstract
NLRP3 inflammasome is a key component of the innate immune system, mediating the activation of caspase-1, and the maturity and secretion of the pro-inflammatory cytokine interleukin (IL)-1beta (IL-1β) and IL-18 to cope with microbial infections and cell injury. The NLRP3 inflammasome is activated by various endogenous danger signals, microorganisms and environmental stimuli, including urate, extracellular adenosine triphosphate (ATP) and cholesterol crystals. Increasing evidence indicates that the abnormal activation of NLRP3 is involved in multiple diseases including renal diseases. Hence, clarifying the mechanism of action of NLRP3 inflammasome in different diseases can help prevent and treat various diseases. Endoplasmic reticulum (ER) is an important organelle which participates in cell homeostasis maintenance and protein quality control. The unfolded protein response (UPR) and ER stress are caused by the excessive accumulation of unfolded or misfolded proteins in ER to recover ER homeostasis. Many factors can cause ER stress, including inflammation, hypoxia, environmental toxins, viral infections, glucose deficiency, changes in Ca2+ level and oxidative stress. The dysfunction of ER stress participates in multiple diseases, such as renal diseases. Many previous studies have shown that NLRP3 inflammasome and ER stress play an important role in renal diseases. However, the relevant mechanisms are not yet fully clear. Herein, we focus on the current understanding of the role and mechanism of ER stress and NLRP3 inflammasome in renal diseases, hoping to provide theoretical references for future related researches.
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Affiliation(s)
- Yanting Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China; School of Clinical Medicine, Henan University, Kaifeng, Henan 475004, China
| | - Shiyun Guo
- School of Clinical Medicine, Henan University, Kaifeng, Henan 475004, China
| | - Xiaodi Fu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Qi Zhang
- School of Clinical Medicine, Henan University, Kaifeng, Henan 475004, China
| | - Honggang Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China.
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12
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Jin J, Shang Y, Zheng S, Dai L, Tang J, Bian X, He Q. Exosomes as nanostructures deliver miR-204 in alleviation of mitochondrial dysfunction in diabetic nephropathy through suppressing methyltransferase-like 7A-mediated CIDEC N6-methyladenosine methylation. Aging (Albany NY) 2024; 16:3302-3331. [PMID: 38334961 PMCID: PMC10929828 DOI: 10.18632/aging.205535] [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: 10/13/2023] [Accepted: 01/03/2024] [Indexed: 02/10/2024]
Abstract
OBJECTIVE The exosomal cargo mainly comprises proteins, lipids, and microRNAs (miRNAs). Among these, miRNAs undertake multiple biological effects of exosomes (Exos). Some stem cell-derived exosomal miRNAs have shown the potential to treat diabetic nephropathy (DN). However, there is little research into the therapeutic effects of adipose-derived stem cell (ADSC)-derived exosomal miRNAs on DN. We aimed to explore the potential of miR-204-modified ADSC-derived Exos to mitigate DN. METHODS Exos were extracted and identified from ADSCs. Histopathological injury, oxidative stress (OS), mitochondrial function, cell viability, and apoptosis were assessed to explore the effects of ADSC-derived Exos on DN. For mechanism exploration, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure miR-204, methyltransferase (METTL3, METTL14, and METTL7A), and CIDEC. Also, CIDEC m6A methylation and miR-204-METTL7A, and METTL7A-CIDEC interactions were determined. RESULTS Initially, OS-induced mitochondrial dysfunction was observed in DN rats. ADSC-derived Exos inhibited histopathological injury, cell apoptosis, OS, and mitochondrial dysfunction in DN rats. The similar therapeutic effects of ADSC-derived Exos were detected in the in vitro model. Intriguingly, miR-204 was released by ADSC-derived Exos and its upregulation enhanced the anti-DN effects of Exos. Mechanically, miR-204 reduced METTL7A expression to CIDEC m6A methylation, thus suppressing OS and mitochondrial dysfunction. CONCLUSIONS ADSC-derived exosomal miR-204 rescued OS-induced mitochondrial dysfunction by inhibiting METTL7A-mediated CIDEC m6A methylation. This study first revealed the significant role of ADSC-derived exosomal miR-204 in DN, paving the way for the development of novel therapeutic strategies to improve the clinical outcomes of DN patients.
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Affiliation(s)
- Juan Jin
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Yiwei Shang
- Clinical School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310004, China
| | - Siqiang Zheng
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Limiao Dai
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Jiyu Tang
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Xueyan Bian
- Department of Nephrology, Ningbo First Hospital, Ningbo, Zhejiang 315010, China
| | - Qiang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
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13
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Wang G, Deng J, Hua Z. Crocin protects against endoplasmic reticulum stress-related tubular injury in diabetic nephropathy via the activation of the PI3K/AKT/Nrf2 pathway. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:439-446. [PMID: 38419890 PMCID: PMC10897564 DOI: 10.22038/ijbms.2023.73385.15942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/26/2023] [Indexed: 03/02/2024]
Abstract
Objectives Diabetic nephropathy (DN) is the main cause of end-stage renal disease, but the current treatment is not satisfactory. Crocin is a major bioactive compound of saffron with antioxidant and anti-endoplasmic reticulum stress (ERS) abilities used to treat diabetes. This study specifically investigated whether crocin has a regulatory role in renal injury in DN. Materials and Methods The experiment was divided into control, (db/m mice), model (db/db mice), and experimental groups (db/db mice were intraperitoneally injected with 40 mg/kg crocin). Renal function-related indicators (Scr, BUN, FBG, UP, TG, TC, ALT, and AST) and oxidative stress-related indicators (ROS, MDA, GSH, SOD, and CAT) were assessed. The pathological changes of renal tissues were confirmed by HE, Masson, PAS, and TUNEL staining. The levels of ERS-related proteins (GRP78 and CHOP), apoptosis-related proteins, and PI3K/AKT and Nrf2 pathways-related proteins in renal tissue were detected. Results In db/db mice, renal function-related indicators, apoptotic cells of renal tissues, the contents of ROS and MDA as well as the expressions of CHOP, GRP78, and Bax were increased, the degree of renal tissue damage was aggravated, while the contents of GSH, SOD, and CAT, as well as the protein levels of Nrf2, PARP, anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-xl) were decreased compared to the db/m mice. However, crocin treatment reversed the above-mentioned situation. The expressions of the PI3K/AKT and Nrf2 pathways-related proteins were also activated by crocin. Conclusion Crocin inhibited oxidative stress and ERS-induced kidney injury in db/db mice by activating the PI3K/AKT and Nrf2 pathways.
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Affiliation(s)
- Guiying Wang
- Department of Nephrology, Shangyu People's Hospital of Shaoxing, Shaoxing, China
| | - Jiuhon Deng
- Department of Endocrinology, Second People's Hospital of Pingyang County, Wenzhou, China
| | - Zhou Hua
- Department of Nephrology, The People's Hospital of Suichang County, Lishui, China
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14
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Han B, Wang L, Zhang Y, Gu L, Yuan W, Cao W. Baseline anxiety disorders are associated with progression of diabetic kidney disease in type 2 diabetes. Ren Fail 2023; 45:2159431. [PMID: 36632821 PMCID: PMC9848365 DOI: 10.1080/0886022x.2022.2159431] [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: 01/13/2023] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a leading cause of kidney failure worldwide. Anxiety has been associated with disease progression in non-diabetes patients. We aimed to examine the prospective association between anxiety and progression of DKD in type 2 diabetes. METHODS We conducted a prospective cohort study of 2040 participants with type 2 diabetes at the Diabetes Center of Shanghai General Hospital between May 2017 and June 2020. Anxiety disorders at baseline were diagnosed by a structured clinical interview based on the 10th Revision of International Classification of Disease (ICD). Progression of DKD was identified as the transition from one urinary albumin excretion rate (AER) stage to the next or the development of kidney failure during the follow-up period. RESULTS At baseline, 403 (19.8%) had a diagnosis of anxiety disorders, of whom 107 (26.6%) also received a depression diagnosis. During a median follow-up time of 3.2 years, deterioration of the kidney status occurred in 340 (16.7%) individuals. After adjustment for potential confounders including depression or an anxiety × depression interaction term, anxiety disorders were independently related to an increased risk of progression of DKD (HR 1.539, 95% CI 1.130-2.095, p = 0.006; HR 1.536, 95% CI 1.111-2.122, p = 0.009, respectively). CONCLUSIONS Anxiety disorders at baseline, independent of possible confounders, were associated with the progression of DKD in type 2 diabetes. Whether therapeutic interventions for anxiety reduce the risk needs to be investigated.
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Affiliation(s)
- Bin Han
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ling Wang
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yueyue Zhang
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lijie Gu
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Weijie Yuan
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China,Weijie Yuan Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China
| | - Wei Cao
- Department of Emergency Medicine, Affiliated Hospital of Jiaxing University, Jiaxing, China,CONTACT Wei Cao Department of Emergency Medicine, Affiliated Hospital of Jiaxing University, 314000, Jiaxing, China
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15
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Amin KN, Rajaguru P, Suzuki T, Sarkar K, Ganesan K, Ramkumar KM. Quantitative proteomic analyses uncover regulatory roles of Nrf2 in human endothelial cells. Cell Stress Chaperones 2023; 28:731-747. [PMID: 37488350 PMCID: PMC10746666 DOI: 10.1007/s12192-023-01366-5] [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: 04/05/2023] [Revised: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator, is the predominant factor in modulating oxidative stress and other cellular signaling responses. Studies from our lab and others highlighted that activation of the Nrf2 pathway by small molecules improves endothelial function by suppressing oxidative and endoplasmic reticulum (ER) stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In the present study, we developed CRISPR/Cas9-mediated Nrf2 knocked-out human endothelial cells, and proteomic signature was studied using LC-MS/MS. We identified 723 unique proteins, of which 361 proteins were found to be differentially regulated and further screened in the Nrf2ome online database, where we identified a highly interconnected signaling network in which 70 proteins directly interact with Nrf2. These proteins were found to regulate some key cellular and metabolic processes in the regulation actin cytoskeleton, ER stress, angiogenesis, inflammation, Hippo signaling pathway, and epidermal growth factor/fibroblast growth factor (EGF/FGF) signaling pathway. Our findings suggest the role of Nrf2 in maintaining endothelium integrity and its relationship with the crucial cellular processes which help develop novel therapeutics against endothelial dysfunction and its associated complications.
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Affiliation(s)
- Karan Naresh Amin
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Palanichamy Rajaguru
- Department of Biotechnology, Central University of Tamil Nadu, Tiruvarur, 610005, India
| | - Takayoshi Suzuki
- Division Cellular and Gene Therapy Products, National Institute of Health Sciences, Setagaya-Ku, Tokyo, 158-8501, Japan
| | - Koustav Sarkar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Kumar Ganesan
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Hong Kong, 999077, China
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India.
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16
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Zheng Y, Zhang Z, Zheng D, Yi P, Wang S. METTL14 promotes the development of diabetic kidney disease by regulating m 6A modification of TUG1. Acta Diabetol 2023; 60:1567-1580. [PMID: 37428236 DOI: 10.1007/s00592-023-02145-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/19/2023] [Indexed: 07/11/2023]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is one of the most common diabetic complications. Endoplasmic reticulum stress (ERS) is an important step for renal tubular epithelial cell apoptosis during DKD progression. Herein, the role and regulatory mechanism of METTL14 in ERS during DKD progression were investigated. METHODS DKD animal and cell models were established by streptozotocin (STZ) and high glucose (HG), respectively. HE and Masson staining were performed to analyze renal lesions in DKD mouse. Cell viability and proliferation were determined by MTT and EdU staining, respectively. HK2 cell apoptosis was analyzed by flow cytometry. TUG1 m6A level was determined by Me-RIP. The interaction between TUG1, LIN28B and MAPK1 was analyzed by RIP and RNA pull-down assays. RESULTS HG stimulation promoted apoptosis and increased ERS marker proteins (GRP78, CHOP and caspase12) expression in HK2 cells, while these changes were reversed by METTL14 knockdown. METTL14 inhibited TUG1 stability and expression level in an m6A-dependent manner. As expected, TUG1 knockdown abrogated METTL14 knockdown's inhibition on HG-induced HK2 cell apoptosis and ERS. In addition, TUG1 inactivated MAPK1/ERK signaling by binding with LIN28B. And TUG1 overexpression's repression on HG-induced HK2 cell apoptosis and ERS was abrogated by MAPK1 signaling activation. Meanwhile, METTL14 knockdown or TUG1 overexpression protected against STZ-induced renal lesions and renal fibrosis in DKD mouse. CONCLUSION METTL14 promoted renal tubular epithelial cell apoptosis and ERS by activating MAPK/ERK pathway through m6A modification of TUG1, thereby accelerating DKD progression.
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Affiliation(s)
- Yingying Zheng
- Health Management Center, Weifang People's Hospital, Weifang Medical University, Weifang, 261041, Shandong Province, People's Republic of China
| | - Zhengjun Zhang
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong Province, People's Republic of China
| | - Dejie Zheng
- Health Management Center, Weifang People's Hospital, Weifang Medical University, Weifang, 261041, Shandong Province, People's Republic of China
| | - Pengfei Yi
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong Province, People's Republic of China
| | - Shaoqiang Wang
- Department of Thoracic Surgery, Weifang People's Hospital, Weifang Medical University, Kuiwen District, No. 151, Guangwen Street, Weifang, 261041, Shandong Province, People's Republic of China.
- Department of Scientific Research Management, Weifang People's Hospital, Weifang Medical University, Weifang, 261041, Shandong Province, People's Republic of China.
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17
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Fang H, Peng Z, Tan B, Peng N, Li B, He D, Xu M, Yang Z. The involvement of PDIA2 gene in the progression of renal cell carcinoma is potentially through regulation of JNK signaling pathway. Clin Transl Oncol 2023; 25:2938-2949. [PMID: 37017923 DOI: 10.1007/s12094-023-03158-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] [Received: 01/20/2023] [Accepted: 03/16/2023] [Indexed: 04/06/2023]
Abstract
Renal cell carcinoma (RCC) with poor prognosis and high incidence rate is a common malignant disease. Current therapies could bring little benefit for the patients with advanced-stage RCC. PDIA2 is an isomerase responsible for protein folding and its role in cancer including RCC is under investigation. In this study, we found that PDIA2 was expressed much higher in RCC tissues than the control but the methylation level of PDIA2 promoter was lower based on the TCGA data. Patients with higher PDIA2 expression exerted worse survival. In clinical specimen, PDIA2 expression was correlated to patients' clinical factors such as TNM stage (I/II vs III/IV, p = 0.025) and tumor size (≤ 7 cm vs > 7 cm, p = 0.004). Moreover, K-M analysis showed that PDIA2 was associated with patients' survival in RCC. PDIA2 was expressed much higher in cancer cells A498 than 786-O than that in 293 T cells. After PDIA2 was knocked down, cell proliferation, migration and invasion was potently inhibited. But cell apoptotic rate increased reversely. Furthermore, the efficacy of Sunitinib on RCC cells was strengthened after PDIA2 knockdown. In addition, knockdown of PDIA2 gene leaded to downregulation of levels of JNK1/2, phosphorylated JNK1/2, c-JUN, and Stat3. But this inhibition was partially released when JNK1/2 was overexpressed. In consistent, cell proliferation was also partially recovered. In summary, PDIA2 plays important role in progression of RCC and JNK signaling pathway might be regulated by PDIA2. This study suggests PDIA2 as a candidate target for therapy of RCC.
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Affiliation(s)
- Huilong Fang
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China
| | - Zhonglu Peng
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China
| | - Bin Tan
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China
| | - Nan Peng
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China
| | - Biao Li
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China
| | - Dongyang He
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China.
| | - Mingjie Xu
- Medical Research and Laboratory Diagnostic Center, Jinan Central Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, 105 Jiefang Road, Jinan, Shandong, 250013, People's Republic of China.
| | - Zhiying Yang
- School of Basic Medical Sciences, Xiangnan University, Street Chenzhou No. 889, Chenzhou, 423000, China.
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18
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Su J, Peng J, Wang L, Xie H, Zhou Y, Chen H, Shi Y, Guo Y, Zheng Y, Guo Y, Dong Z, Zhang X, Liu H. Identification of endoplasmic reticulum stress-related biomarkers of diabetes nephropathy based on bioinformatics and machine learning. Front Endocrinol (Lausanne) 2023; 14:1206154. [PMID: 37745718 PMCID: PMC10513048 DOI: 10.3389/fendo.2023.1206154] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 05/24/2023] [Indexed: 09/26/2023] Open
Abstract
Backgrounds Diabetes nephropathy (DN) is a growing public health concern worldwide. Renal dysfunction impairment in DN is intimately linked to ER stress and its related signaling pathways. Nonetheless, the underlying mechanism and biomarkers for this function of ER stress in the DN remain unknown. Methods Microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database, and ER stress-related genes (ERSRGs) were downloaded from the MSigDB and GeneCards database. We identified hub ERSRGs for DN progression by intersecting ERSRGs with differentially expressed genes and significant genes in WGCNA, followed by a functional analysis. After analyzing hub ERSRGs with three machine learning techniques and taking the intersection, we did external validation as well as developed a DN diagnostic model based on the characteristic genes. Immune infiltration was performed using CIBERSORT. Moreover, patients with DN were then categorized using a consensus clustering approach. Eventually, the candidate ERSRGs-specific small-molecule compounds were defined by CMap. Results Several biological pathways driving pathological injury of DN and disordered levels of immune infiltration were revealed in the DN microarray datasets and strongly related to deregulated ERSRGs by bioinformatics multi-chip integration. Moreover, CDKN1B, EGR1, FKBP5, GDF15, and MARCKS were identified as ER stress signature genes associated with DN by machine learning algorithms, demonstrating their potential as DN biomarkers. Conclusions Our research sheds fresh light on the function of ER stress in DN pathophysiology and the development of early diagnostic and ER stress-related treatment targets in patients with DN.
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Affiliation(s)
- Jiaming Su
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Jing Peng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lin Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Huidi Xie
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Ying Zhou
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Haimin Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yang Shi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yan Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yicheng Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yuxin Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Zhaoxi Dong
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xianhui Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Hongfang Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
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19
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Su BL, Wang LL, Zhang LY, Zhang S, Li Q, Chen GY. Potential role of microRNA-503 in Icariin-mediated prevention of high glucose-induced endoplasmic reticulum stress. World J Diabetes 2023; 14:1234-1248. [PMID: 37664468 PMCID: PMC10473951 DOI: 10.4239/wjd.v14.i8.1234] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/12/2023] [Accepted: 07/07/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Dysregulated microRNA (miRNA) is crucial in the progression of diabetic nephropathy (DN). AIM To investigate the potential molecular mechanism of Icariin (ICA) in regulating endoplasmic reticulum (ER) stress-mediated apoptosis in high glucose (HG)-induced primary rat kidney cells (PRKs), with emphasis on the role of miR-503 and sirtuin 4 (SIRT4) in this process. METHODS Single intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model. Glucose-treated PRKs were used as an in vitro HG model. An immunofluorescence assay identified isolated PRKs. Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis, respectively. Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stress-related proteins. Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed. RESULTS ICA treatment alleviated the upregulated miR-503 expression in vivo (DN) and in vitro (HG). Mechanistically, ICA reduced HG-induced miR-503 overexpression, thereby counteracting its function in downregulating SIRT4 levels. ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury. CONCLUSION ICA reduced HG-mediated inhibition of cell viability, promotion of apoptosis, and ER stress in PRKs. These effects involved regulation of the miR-503/SIRT4 axis. These findings indicate the potential of ICA to treat DN, and implicate miR-503 as a viable target for therapeutic interventions in DN.
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Affiliation(s)
- Bao-Lin Su
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Liang-Liang Wang
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Liang-You Zhang
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Shu Zhang
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Qiang Li
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Gang-Yi Chen
- Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
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20
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Wei M, Liu X, Li M, Tian X, Feng M, Pang B, Fang Z, Wei J. The role of Chinese herbal medicine in the treatment of diabetic nephropathy by regulating endoplasmic reticulum stress. Front Pharmacol 2023; 14:1174415. [PMID: 37435493 PMCID: PMC10331427 DOI: 10.3389/fphar.2023.1174415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 06/15/2023] [Indexed: 07/13/2023] Open
Abstract
Diabetic nephropathy (DN), a prevalent microvascular complication of diabetes mellitus, is the primary contributor to end-stage renal disease in developed countries. Existing clinical interventions for DN encompass lifestyle modifications, blood glucose regulation, blood pressure reduction, lipid management, and avoidance of nephrotoxic medications. Despite these measures, a significant number of patients progress to end-stage renal disease, underscoring the need for additional therapeutic strategies. The endoplasmic reticulum (ER) stress response, a cellular defense mechanism in eukaryotic cells, has been implicated in DN pathogenesis. Moderate ER stress can enhance cell survival, whereas severe or prolonged ER stress may trigger apoptosis. As such, the role of ER stress in DN presents a potential avenue for therapeutic modulation. Chinese herbal medicine, a staple in Chinese healthcare, has emerged as a promising intervention for DN. Existing research suggests that some herbal remedies may confer renoprotective benefits through the modulation of ER stress. This review explores the involvement of ER stress in the pathogenesis of DN and the advancements in Chinese herbal medicine for ER stress regulation, aiming to inspire new clinical strategies for the prevention and management of DN.
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Affiliation(s)
- Maoying Wei
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xingxing Liu
- Department of Emergency, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingdi Li
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaochan Tian
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingyue Feng
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Boxian Pang
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zeyang Fang
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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21
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Wei M, Liu X, Tan Z, Tian X, Li M, Wei J. Ferroptosis: a new strategy for Chinese herbal medicine treatment of diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:1188003. [PMID: 37361521 PMCID: PMC10289168 DOI: 10.3389/fendo.2023.1188003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. It has become a leading cause of death in patients with diabetes and end-stage renal disease. Ferroptosis is a newly discovered pattern of programmed cell death. Its main manifestation is the excessive accumulation of intracellular iron ion-dependent lipid peroxides. Recent studies have shown that ferroptosis is an important driving factor in the onset and development of DN. Ferroptosis is closely associated with renal intrinsic cell (including renal tubular epithelial cells, podocytes, and mesangial cells) damage in diabetes. Chinese herbal medicine is widely used in the treatment of DN, with a long history and definite curative effect. Accumulating evidence suggests that Chinese herbal medicine can modulate ferroptosis in renal intrinsic cells and show great potential for improving DN. In this review, we outline the key regulators and pathways of ferroptosis in DN and summarize the herbs, mainly monomers and extracts, that target the inhibition of ferroptosis.
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Affiliation(s)
- Maoying Wei
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xingxing Liu
- Department of Emergency, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhijuan Tan
- Department of Traditional Chinese Medicine, The Seventh Hospital of Xingtai, Xingtai, Heibei, China
| | - Xiaochan Tian
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingdi Li
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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22
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Zhang R, Bian C, Gao J, Ren H. Endoplasmic reticulum stress in diabetic kidney disease: adaptation and apoptosis after three UPR pathways. Apoptosis 2023:10.1007/s10495-023-01858-w. [PMID: 37285056 DOI: 10.1007/s10495-023-01858-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2023] [Indexed: 06/08/2023]
Abstract
Diabetes kidney disease (DKD) is one of the common chronic microvascular complications of diabetes, which has become the most important cause of modern chronic kidney disease beyond chronic glomerulonephritis. The endoplasmic reticulum is one of the largest organelles, and endoplasmic reticulum stress (ERS) is the basic mechanism of metabolic disorder in all organs and tissues. Under the stimulation of stress-induced factors, the endoplasmic reticulum, as a trophic receptor, regulates adaptive and apoptotic ERS through molecular chaperones and three unfolded protein reaction (UPR) pathways, thereby regulating diabetic renal damage. Therefore, three pathway factors have different expressions in different sections of renal tissues. This study deeply discussed the specific reagents, animals, cells, and clinical models related to ERS in DKD, and reviewed ERS-related three pathways on DKD with glomerular filtration membrane, renal tubular reabsorption, and other pathological lesions of different renal tissues, as well as the molecular biological mechanisms related to the balance of adaption and apoptosis by searching and sorting out MeSH subject words from PubMed database.
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Affiliation(s)
- Ruijing Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China
| | - Che Bian
- Department of Endocrinology and Metabolism, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jing Gao
- Department of Cardiology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huiwen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China.
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23
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Zhong Y, Wang L, Jin R, Liu J, Luo R, Zhang Y, Zhu L, Peng X. Diosgenin Inhibits ROS Generation by Modulating NOX4 and Mitochondrial Respiratory Chain and Suppresses Apoptosis in Diabetic Nephropathy. Nutrients 2023; 15:2164. [PMID: 37432297 PMCID: PMC10181383 DOI: 10.3390/nu15092164] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/22/2023] [Accepted: 04/25/2023] [Indexed: 07/12/2023] Open
Abstract
Diosgenin (DIO) is a dietary steroid sapogenin possessing multiple biological functions, such as the amelioration of diabetes. However, the remission effect of DIO on diabetic nephropathy (DN) underlying oxidative stress and cell apoptosis remains unclear. Here, the effect of DIO on ROS generation and its induced cell apoptosis was studied in vitro and in vivo. Renal proximal tubular epithelial (HK-2) cells were treated with DIO (1, 2, 4 µM) under high glucose (HG, 30 mM) conditions. DN rats were induced by a high-fat diet combined with streptozotocin, followed by administration of DIO for 8 weeks. Our data suggested that DIO relieved the decline of HK-2 cell viability and renal pathological damage in DN rats. DIO also relieved ROS (O2- and H2O2) production. Mechanistically, DIO inhibited the expression of NOX4 and restored mitochondrial respiratory chain (MRC) complex I-V expressions. Further, DIO inhibited mitochondrial apoptosis by ameliorating mitochondrial membrane potential (MtMP) and down-regulating the expressions of CytC, Apaf-1, caspase 3, and caspase 9, while up-regulating Bcl2 expression. Moreover, the ER stress and its associated cell apoptosis were inhibited through decreasing PERK, p-PERK, ATF4, IRE1, p-CHOP, and caspase 12 expressions. Collectively, DIO inhibited ROS production by modulating NOX4 and MRC complexes, which then suppressed apoptosis regulated by mitochondria and ER stress, thereby attenuating DN.
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Affiliation(s)
- Yujie Zhong
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
| | - Lei Wang
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
| | - Ruyi Jin
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
| | - Jiayu Liu
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
| | - Ruilin Luo
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
| | - Yinghan Zhang
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
| | - Lin Zhu
- Qinling National Botanical Garden, Xi’an 710061, China
| | - Xiaoli Peng
- College of Food Science and Engineering, Northwest A&F University, Xianyang 712100, China
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24
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Azarova I, Klyosova E, Polonikov A. Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes. Biomedicines 2023; 11:981. [PMID: 36979960 PMCID: PMC10046239 DOI: 10.3390/biomedicines11030981] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/12/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Single nucleotide polymorphisms (SNP) in the RAC1 (Rac family small GTPase 1) gene have recently been linked to type 2 diabetes (T2D) and hyperglycemia due to their contribution to impaired redox homeostasis. The present study was designed to determine whether the common SNPs of the RAC1 gene are associated with diabetic complications such as neuropathy (DN), retinopathy (DR), nephropathy, angiopathy of the lower extremities (DA), and diabetic foot syndrome. A total of 1470 DNA samples from T2D patients were genotyped for six common SNPs by the MassArray Analyzer-4 system. The genotype rs7784465-T/C of RAC1 was associated with an increased risk of DR (p = 0.016) and DA (p = 0.03) in males, as well as with DR in females (p = 0.01). Furthermore, the SNP rs836478 showed an association with DR (p = 0.005) and DN (p = 0.025) in males, whereas the SNP rs10238136 was associated with DA in females (p = 0.002). In total, three RAC1 haplotypes showed significant associations (FDR < 0.05) with T2D complications in a sex-specific manner. The study's findings demonstrate, for the first time, that the RAC1 gene's polymorphisms represent novel and sex-specific markers of neuropathy and microvascular complications in type 2 diabetes, and that the gene could be a new target for the pharmacological inhibition of oxidative stress as a means of preventing diabetic complications.
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Affiliation(s)
- Iuliia Azarova
- Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia;
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia or
| | - Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia or
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia
| | - Alexey Polonikov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia
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25
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Xing B, Pu C, Chen Y, Sheng Y, Zhang B, Cui J, Wu G, Zhao Y. Insights into the characteristics of primary radioresistant cervical cancer using single-cell transcriptomics. Hum Cell 2023; 36:1135-1146. [PMID: 36867313 PMCID: PMC10110719 DOI: 10.1007/s13577-023-00882-x] [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: 09/20/2022] [Accepted: 02/11/2023] [Indexed: 03/04/2023]
Abstract
Radioresistance is a major cause of radiotherapy failure among patients with cervical cancer (CC), the fourth most common cause of cancer mortality in women worldwide. Traditional CC cell lines lose intra-tumoral heterogeneity, posing a challenge for radioresistance research. Meanwhile, conditional reprogramming (CR) maintains intra-tumoral heterogeneity and complexity, as well as the genomic and clinical characteristics of original cells and tissues. Three radioresistant and two radiosensitive primary CC cell lines were developed under CR conditions from patient specimens, and their characteristics were verified via immunofluorescence, growth kinetics, clone forming assay, xenografting, and immunohistochemistry. The CR cell lines had homogenous characteristics with original tumor tissues and maintained radiosensitivity in vitro and in vivo, while also maintaining intra-tumoral heterogeneity according to single-cell RNA sequencing analysis. Upon further investigation, 20.83% of cells in radioresistant CR cell lines aggregated in the G2/M cell cycle phase, which is sensitive to radiation, compared to 38.1% of cells in radiosensitive CR cell lines. This study established three radioresistant and two radiosensitive CC cell lines through CR, which will benefit further research investigating radiosensitivity in CC. Our present study may provide an ideal model for research on development of radioresistance and potential therapeutic targets in CC.
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Affiliation(s)
- Biyuan Xing
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Congli Pu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yunshang Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuhan Sheng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Baofang Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jie Cui
- CAS Key Laboratory of Molecular Virology & Immunology, Center for Biosafety Mega-Science, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
| | - Gang Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yingchao Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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26
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Vijayalalitha R, Archita T, Juanitaa GR, Jayasuriya R, Amin KN, Ramkumar KM. Role of Long Non-Coding RNA in Regulating ER Stress Response to the Progression of Diabetic Complications. Curr Gene Ther 2023; 23:96-110. [PMID: 35927920 DOI: 10.2174/1566523222666220801141450] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/08/2022] [Accepted: 04/22/2022] [Indexed: 11/22/2022]
Abstract
Chronic hyperglycemia damages the nerves and blood vessels, culminating in other vascular complications. Such complications enhance cytokine, oxidative and endoplasmic reticulum (ER) stress. ER is the primary organelle where proteins are synthesised and attains confirmatory changes before its site of destination. Perturbation of ER homeostasis activates signaling sensors within its lumen, the unfolded protein response (UPR) that orchestrates ER stress and is extensively studied. Increased ER stress markers are reported in diabetic complications in addition to lncRNA that acts as an upstream marker inducing ER stress response. This review focuses on the mechanisms of lncRNA that regulate ER stress markers, especially during the progression of diabetic complications. Through this systemic review, we showcase the dysfunctional lncRNAs that act as a leading cause of ER stress response to the progression of diabetic complications.
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Affiliation(s)
- Ramanarayanan Vijayalalitha
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Tca Archita
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - George Raj Juanitaa
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Ravichandran Jayasuriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Karan Naresh Amin
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
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27
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Prasad M K, Mohandas S, Kunka Mohanram R. Role of ferroptosis inhibitors in the management of diabetes. Biofactors 2022; 49:270-296. [PMID: 36468443 DOI: 10.1002/biof.1920] [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: 09/08/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022]
Abstract
Ferroptosis, the iron-dependent, lipid peroxide-mediated cell death, has garnered attention due to its critical involvement in crucial physiological and pathological cellular processes. Indeed, several studies have attributed its role in developing a range of disorders, including diabetes. As accumulating evidence further the understanding of ferroptotic mechanisms, the impact this specialized mode of cell death has on diabetic pathogenesis is still unclear. Several in vivo and in vitro studies have highlighted the association of ferroptosis with beta-cell death and insulin resistance, supported by observations of marked alterations in ferroptotic markers in experimental diabetes models. The constant improvement in understanding ferroptosis in diabetes has demonstrated it as a potential therapeutic target in diabetic management. In this regard, ferroptosis inhibitors promise to rescue pancreatic beta-cell function and alleviate diabetes and its complications. This review article elucidates the key ferroptotic pathways that mediate beta-cell death in diabetes, and its complications. In particular, we share our insight into the cross talk between ferroptosis and other hallmark pathogenic mediators such as oxidative and endoplasmic reticulum stress regulators relevant to diabetes progression. Further, we extensively summarize the recent developments on the role of ferroptosis inhibitors and their therapeutic action in alleviating diabetes and its complications.
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Affiliation(s)
- Krishna Prasad M
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Ramkumar Kunka Mohanram
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
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28
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Sonthalia M, Roy BS, Chandrawanshi D, Ganesh GV, Jayasuriya R, Mohandas S, Rajagopal S, Ramkumar KM. Histone deacetylase inhibitors as antidiabetic agents: Advances and opportunities. Eur J Pharmacol 2022; 935:175328. [DOI: 10.1016/j.ejphar.2022.175328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 10/08/2022] [Accepted: 10/12/2022] [Indexed: 11/26/2022]
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29
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Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells. Int J Mol Sci 2022; 23:ijms231911215. [PMID: 36232514 PMCID: PMC9570341 DOI: 10.3390/ijms231911215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1β and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.
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30
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Molecular Mechanistic Pathways Targeted by Natural Compounds in the Prevention and Treatment of Diabetic Kidney Disease. Molecules 2022; 27:molecules27196221. [PMID: 36234757 PMCID: PMC9571643 DOI: 10.3390/molecules27196221] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 12/03/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and its prevalence is still growing rapidly. However, the efficient therapies for this kidney disease are still limited. The pathogenesis of DKD involves glucotoxicity, lipotoxicity, inflammation, oxidative stress, and renal fibrosis. Glucotoxicity and lipotoxicity can cause oxidative stress, which can lead to inflammation and aggravate renal fibrosis. In this review, we have focused on in vitro and in vivo experiments to investigate the mechanistic pathways by which natural compounds exert their effects against the progression of DKD. The accumulated and collected data revealed that some natural compounds could regulate inflammation, oxidative stress, renal fibrosis, and activate autophagy, thereby protecting the kidney. The main pathways targeted by these reviewed compounds include the Nrf2 signaling pathway, NF-κB signaling pathway, TGF-β signaling pathway, NLRP3 inflammasome, autophagy, glycolipid metabolism and ER stress. This review presented an updated overview of the potential benefits of these natural compounds for the prevention and treatment of DKD progression, aimed to provide new potential therapeutic lead compounds and references for the innovative drug development and clinical treatment of DKD.
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31
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Yang M, Luo S, Yang J, Chen W, He L, Liu D, Zhao L, Wang X. Crosstalk between the liver and kidney in diabetic nephropathy. Eur J Pharmacol 2022; 931:175219. [PMID: 35987257 DOI: 10.1016/j.ejphar.2022.175219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 08/09/2022] [Accepted: 08/14/2022] [Indexed: 11/26/2022]
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes, and its pathogenesis has not been fully elucidated. Recently, communication between organs has gradually become a new focus in the study of diseases pathogenesis, and abnormal interorgan communication has been proven to be involved in the occurrence and progression of many diseases. As an important metabolic organ in the human body, the liver plays an important role in maintaining homeostasis in humans. The liver secretes a series of proteins called hepatokines that affect adjacent and distal organs through paracrine or endocrine signaling pathways. In this review, we summarize some of the hepatokines identified to date and describe their roles in DN to discuss the possibility that the liver-renal axis is potentially useful as a therapeutic target for DN. We summarize the important hepatokines identified thus far and discuss their relationship with DN. We propose for the first time that the "liver-renal axis" is a potential therapeutic target in individuals with DN.
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Affiliation(s)
- Ming Yang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Di Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Li Zhao
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, China
| | - Xi Wang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Chen F, Ge Z, Li N, Yu Z, Wu R, Zhao Y, He X, Cai G. TUDCA protects against tunicamycin-induced apoptosis of dorsal root ganglion neurons by suppressing activation of ER stress. Exp Ther Med 2022; 24:509. [PMID: 35837048 PMCID: PMC9257946 DOI: 10.3892/etm.2022.11436] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/05/2022] [Indexed: 11/29/2022] Open
Abstract
The existence of endoplasmic reticulum (ER) stress in neurodegenerative diseases has been well established. Tauroursodeoxycholic acid (TUDCA) is a bile acid taurine conjugate derived from ursodeoxycholic acid, which has been reported to exert cytoprotective effects on several types of cells by inhibiting ER stress. The present study explored the effects of TUDCA on primary cultured rat dorsal root ganglion (DRG) neurons. Cell viability and apoptosis of DRG neurons treated with TUDCA and tunicamycin were detected by CellTiter-Blue assay and TUNEL staining, respectively. The protein levels and phosphorylation of apoptosis and ERS-related signaling pathway molecules were detected by western blot, and the mRNA levels of related genes were assessed by reverse transcription-quantitative PCR. Notably, TUDCA had no significant cytotoxic effect on DRG neurons at concentrations ≤250 µM. In addition, the apoptosis induced by tunicamycin exposure was markedly suppressed by TUDCA, as indicated by the percentage of TUNEL-positive cells, the activities of caspases and the changes in expression levels of critical apoptosis factors. Furthermore, the cytotoxicity of tunicamycin in DRG neurons was accompanied by an increase in malondialdehyde (MDA) content, reactive oxygen species (ROS) and lactate dehydrogenase (LDH) production, and a decrease in glutathione (GSH) levels. The changes in oxidative stress-related factors (ROS, LDH, MDA and GSH) were reversed by TUDCA. Furthermore, as determined by western blotting, the increase in C/EBP homologous protein, glucose-regulated protein 78 and cleaved caspase-12 expression following tunicamycin treatment suggested the activation of ER stress. Downregulation of ER stress components and unfolded protein response sensors by TUDCA confirmed the implication of ER stress in the effects of TUDCA on DRG neurons. In conclusion, the present study indicated that TUDCA may protect against tunicamycin-induced DRG apoptosis by suppressing the activation of ER stress. The protective effect and the therapeutic value of TUDCA in nervous system injury require further study in animal models.
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Affiliation(s)
- Fangyi Chen
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Zhe Ge
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Nan Li
- Department of Stomatology, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Zuochong Yu
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Rongbo Wu
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Yan Zhao
- Department of Clinical Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Xianwei He
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
| | - Guoping Cai
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
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Double-Sided Nano-ZnO: Superior Antibacterial Properties and Induced Hepatotoxicity in Zebrafish Embryos. TOXICS 2022; 10:toxics10030144. [PMID: 35324769 PMCID: PMC8950655 DOI: 10.3390/toxics10030144] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/07/2022] [Accepted: 03/16/2022] [Indexed: 12/30/2022]
Abstract
Zinc oxide nanoparticles (Nano-ZnO) have been widely used in the food, cosmetics, and biomedical fields due to their excellent antibacterial and antioxidant properties. However, with the widespread application of Nano-ZnO, Nano-ZnO inevitably enters the environment and living organisms, causing harm to human health and ecosystem safety. Therefore, the biosafety and toxicological issues of Nano-ZnO are gradually being emphasized. Our study found that Nano-ZnO has superior antibacterial properties compared to ofloxacin in the fight against Staphylococcus aureus (S. aureus). Given that ofloxacin can inhibit bacterial-induced inflammation, we constructed a model of bacterial inflammation using S. aureus in zebrafish. We found that Nano-ZnO inhibited the NF-κB-mediated inflammatory signaling pathway. However, in the process, we found that Nano-ZnO caused hepatic steatosis in zebrafish. This suggested that Nano-ZnO had a certain hepatotoxicity, but did not affect liver development. Subsequently, we investigated the mechanism of hepatotoxicity produced by Nano-ZnO. Nano-ZnO triggered oxidative stress in the liver by generating ROS, which then induced endoplasmic reticulum stress to occur. It further activated srebp and its downstream genes fasn and acc1, which promoted the accumulation of fatty acid synthesis and the development of steatosis, leading to the development of nonalcoholic fatty liver disease (NAFLD). To address the hepatotoxicity of Nano-ZnO, we added carbon dots for the treatment of NAFLD. The carbon dots were found to normalize the steatotic liver. This provided a new strategy to address the hepatotoxicity caused by Nano-ZnO. In this work, we systematically analyzed the antibacterial advantages of Nano-ZnO in vivo and in vitro, explored the mechanism of Nano-ZnO hepatotoxicity, and proposed a new method to treat Nano-ZnO hepatotoxicity.
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Zhong Y, Liu J, Sun D, Guo T, Yao Y, Xia X, Shi C, Peng X. Dioscin relieves diabetic nephropathy via suppressing oxidative stress and apoptosis, and improving mitochondrial quality and quantity control. Food Funct 2022; 13:3660-3673. [PMID: 35262539 DOI: 10.1039/d1fo02733f] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Dioscin is a steroidal saponin isolated from various kinds of vegetables and herbs and possesses various biological activities. In this study, the protective effect of dioscin on diabetic nephropathy (DN) was explored. Dioscin and metformin (positive control) were administered orally to diabetic rats daily for 8 weeks. The biochemistry parameters, pancreas and kidney histological changes, oxidative stress, inflammation, apoptosis, autophagy, and mitochondrial quality and quantity control (mitophagy and mitochondrial fission/fusion) were measured. Our results showed that dioscin effectively reduced blood glucose, pancreatic injury, renal function markers and renal pathological changes in DN rat kidneys. Dioscin reduced O2- and H2O2 levels, decreased MDA levels, enhanced antioxidant enzyme (SOD, CAT) activities, and reduced inflammatory factor expressions. Moreover, NOX4 expression and the disorder of the mitochondrial respiratory chain were reversed by dioscin. Furthermore, apoptosis mediated by the mitochondria and ER stress was inhibited by dioscin through downregulating the expressions of Bax, CytC, Apaf-1, caspase 9, p-PERK, p-EIF2α, IRE1, p-IRE1, XBP1s, ATF4, p-CHOP and caspase 12. In addition, autophagy was enhanced by dioscin via an AMPK-mTOR pathway. Mitophagy and mitochondrial fission/fusion belong to the mitochondrial quality and quantity control process, which was improved by dioscin via regulating Parkin, PINK1, DRP1, p-DRP1 and MFN2 expressions. Collectively, these results suggested that dioscin protected against DN through inhibiting oxidative stress, inflammation, and apoptosis mediated by the mitochondria and ER stress. Autophagy and mitochondrial quality and quantity control (mitophagy and mitochondrial fission/fusion) were also improved by dioscin.
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Affiliation(s)
- Yujie Zhong
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Jiayu Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Dianjun Sun
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Tianmin Guo
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Yanpeng Yao
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Xiaodong Xia
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Chao Shi
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Xiaoli Peng
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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Prasad M K, Mohandas S, Ramkumar KM. Role of ER stress inhibitors in the management of diabetes. Eur J Pharmacol 2022; 922:174893. [DOI: 10.1016/j.ejphar.2022.174893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 12/14/2022]
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Rehni AK, Cho S, Dave KR. Ischemic brain injury in diabetes and endoplasmic reticulum stress. Neurochem Int 2022; 152:105219. [PMID: 34736936 PMCID: PMC8918032 DOI: 10.1016/j.neuint.2021.105219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 10/07/2021] [Accepted: 10/29/2021] [Indexed: 01/03/2023]
Abstract
Diabetes is a widespread disease characterized by high blood glucose levels due to abnormal insulin activity, production, or both. Chronic diabetes causes many secondary complications including cardiovascular disease: a life-threatening complication. Cerebral ischemia-related mortality, morbidity, and the extent of brain injury are high in diabetes. However, the mechanism of increase in ischemic brain injury during diabetes is not well understood. Multiple mechanisms mediate diabetic hyperglycemia and hypoglycemia-induced increase in ischemic brain injury. Endoplasmic reticulum (ER) stress mediates both brain injury as well as brain protection after ischemia-reperfusion injury. The pathways of ER stress are modulated during diabetes. Free radical generation and mitochondrial dysfunction, two of the prominent mechanisms that mediate diabetic increase in ischemic brain injury, are known to stimulate the pathways of ER stress. Increased ischemic brain injury in diabetes is accompanied by a further increase in the activation of ER stress. As there are many metabolic changes associated with diabetes, differential activation of the pathways of ER stress may mediate pronounced ischemic brain injury in subjects suffering from diabetes. We presently discuss the literature on the significance of ER stress in mediating increased ischemia-reperfusion injury in diabetes.
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Affiliation(s)
- Ashish K Rehni
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Sunjoo Cho
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Differential expression of gluconeogenic enzymes in early- and late-stage diabetes: the effect of Citrullus colocynthis (L.) Schrad. Seed extract on hyperglycemia and hyperlipidemia in Wistar-Albino rats model. CLINICAL PHYTOSCIENCE 2021. [DOI: 10.1186/s40816-021-00324-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The medicinal plant Citrullus colocynthis (L.) Schrad. (C. colocynthis) may benefit patients at different phases of diabetes by attuning to contrasting situations. Our primary objective was to find the mechanism(s) behind the antidiabetic/anti-hyperlipidemic effects of C.colocynthis seed aqueous extract (CCAE) in two different stages of type 2 diabetes (T2D) in rats.
Methods
Fasting blood sugar (FBS) levels, body weights, and the degree of impaired glucose tolerance (IGT) were measured in healthy nondiabetic control rats (Con), as well as rats with early and late stages of T2D, denoted as ET2D and LT2D, respectively. CCAE was intraperitoneally (IP) injected for 28 days. In the end, the hepatic mRNA expression levels of the following genes were determined by RT-PCR: glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), insulin-dependent sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), peroxisome proliferator-activated receptor alpha (PPARα), and carnitine palmitoyltransferase I (CPT1). The liver was examined by hematoxylin and eosin (H&E) and Oil-Red O staining. CCAE was partially analyzed by HPLC-DAD.
Results
ET2D and LT2D were characterized by differentially elevated FBS, deteriorated bodyweight, and significant IGT compared to Con. Hepatosteatoses of varying morphologies and higher hepatic expression of G6Pase than PRPCK in ET2D versus the opposite in LT2D further confirmed the divergent nature of metabolic aberrations. At the end of 28 days, the high levels of FBS, alkaline phosphatase (ALP), triglyceride (TG), urea, hepatic protein carbonyl content (PCC), and alanine and aspartate aminotransferases (AST and ALT, respectively) persisted in untreated LT2D. CCAE ameliorated oxidative stress and upregulated PPARα expression in diabetic groups and Con; it downregulated CPT1 expression in the LT2D group. CCAE’s ability to lower FBS and serum and hepatic TG in both ET2D and LT2D indicated its ability to act via different mechanisms. Ferulic acid (Fer A) and rutin hydrate (RH) were detected in CCAE.
Conclusion
CCAE lowered the FBS in ET2D via inhibiting the hepatic G6Pase expression (glycogenolysis). In LT2D, CCAE abated sugar levels by diverting PEPCK activity, preferably towards glyceroneogenesis than gluconeogenesis. The preserved triglyceride/fatty acid (TG/FA) cycle, the upregulated PPARα, and the downregulated CPT1 gene expressions reduced serum and hepatic TG.
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Sánchez‐Navarro A, Martínez‐Rojas MÁ, Caldiño‐Bohn RI, Pérez‐Villalva R, Zambrano E, Castro‐Rodríguez DC, Bobadilla NA. Early triggers of moderately high-fat diet-induced kidney damage. Physiol Rep 2021; 9:e14937. [PMID: 34291592 PMCID: PMC8295594 DOI: 10.14814/phy2.14937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/04/2021] [Indexed: 11/30/2022] Open
Abstract
Most of the obesity murine models inducing renal injury use calorie-enriched foods, where fat represents 60% of the total caloric supply, however, this strategy doubles the standard proportion of fat ingestion in obese patients. Therefore, it is crucial to study the impact of a high-fat intake on kidney physiology that resembles common obesity in humans to understand the trigger mechanisms of the long-term consequences of overweight and obesity. In this study, we analyzed whether chronic feeding with a moderately high fat diet (MHFD) representing 45% of total calories, may induce kidney function and structural injury compared to C57BL/6 mice fed a control diet. After 14 weeks, MHFD induced significant mice obesity. At the functional level, obese mice showed signs of kidney injury characterized by increased albuminuria/creatinine ratio and higher excretion of urinary biomarkers of kidney damage. While, at the structural level, glomerular hypertrophy was observed. Although, we did not detect renal fibrosis, the obese mice exhibited a significant elevation of Tgfb1 mRNA levels. Kidney damage caused by the exposure to MHFD was associated with greater oxidative stress, renal inflammation, higher endoplasmic reticulum (ER)-stress, and disruption of mitochondrial dynamics. In summary, our data demonstrate that obesity induced by a milder fat content diet is enough to establish renal injury, where oxidative stress, inflammation, ER-stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long-term consequences associated with obesity and metabolic syndrome.
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Affiliation(s)
- Andrea Sánchez‐Navarro
- Molecular Physiology UnitInstituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico CityMexico
- Department of NephrologyInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
| | - Miguel Ángel Martínez‐Rojas
- Molecular Physiology UnitInstituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico CityMexico
- Department of NephrologyInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
| | - Rebecca I. Caldiño‐Bohn
- Molecular Physiology UnitInstituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico CityMexico
- Department of NephrologyInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
| | - Rosalba Pérez‐Villalva
- Molecular Physiology UnitInstituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico CityMexico
- Department of NephrologyInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
| | - Elena Zambrano
- Department of Biology of ReproductionInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
| | - Diana C. Castro‐Rodríguez
- Department of Biology of ReproductionInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
- CONACyT‐CátedrasMexico CityMexico
| | - Norma A. Bobadilla
- Molecular Physiology UnitInstituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico CityMexico
- Department of NephrologyInstituto Nacional de Ciencias Médicas y NutriciónSalvador ZubiránMexico CityMexico
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