|
1
|
Chen H, Yang K, Zhang S, Yesitayi G, Ling Y, Gao R, Lyu Y, Wei W, Shi J, Li Y, Ma X, Gao P, Ge J, Sun A. Caspase-12 exhibits non-redundant functions in response to endoplasmic reticulum stress to promote GSDMD-mediated NETosis, leading to thoracic aortic dissection. Transl Res 2025; 278:48-60. [PMID: 40015601 DOI: 10.1016/j.trsl.2025.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Thoracic aortic dissection (TAD) is a highly lethal condition that is characterized by inflammatory cell infiltration. Recent evidence has indicated that Gasdermin D (GSDMD) plays an important role in vascular inflammation and degeneration. However, its effects on neutrophil extracellular trap formation and release (NETosis) during TAD remain unknown. METHODS A TAD mouse model was generated using four-week-old male neutrophil-specific GSDMD-knockout mice (GSDMDF/F; ElaneCre) and dimethyl fumarate (DMF)-treated C57BL/6J mice by administering β-aminopropionitrile monofumarate (BAPN; 1 g/kg/day) in their drinking water for 4 weeks. Immunoprecipitation and immunofluorescence assays were performed to examine the role of the endoplasmic reticulum (ER) and its associated protein, caspase-12, in GSDMD-induced NETosis. RESULTS GSDMD was elevated and co-localized primarily in neutrophils in the aortic tissues of patients with TAD and mice with BAPN-induced TAD. This was accompanied by increased NETosis. Neutrophil-specific GSDMD knockout and the NETosis inhibitor, GSK484, mitigated TAD development in mice. However, GSK484 did not provide additional therapeutic effects against TAD in the neutrophil-specific, GSDMD knockout mice. Mechanistically, ER stress promoted GSDMD cleavage by caspase-4/11, thereby inducing NETosis. Furthermore, caspase-12 exhibited non-redundant functions in the cleavage of GSDMD by caspase-4/11. The GSDMD inhibitor, DMF, partially prevented TAD development. CONCLUSIONS The ER stress/GSDMD/NETosis signaling pathway provides a potential therapeutic target for the prevention and treatment of TAD.
Collapse
Affiliation(s)
- Hanchuan Chen
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China Department of Cardiology, Shanghai, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kun Yang
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shumin Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China Department of Cardiology, Shanghai, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gulinazi Yesitayi
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Yunzhi Ling
- Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fujian, China
| | - Rifeng Gao
- Department of Cardiac Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Yang Lyu
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Wei Wei
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jiaran Shi
- Department of Cardiology, Lihuili Hospital Facilitated to Ningbo University, Zhejiang, China
| | - Yulin Li
- Beijing Anzhen Hospital of Capital Medical University, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Xiang Ma
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Pingjin Gao
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China Department of Cardiology, Shanghai, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
| | - Aijun Sun
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China Department of Cardiology, Shanghai, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
| |
Collapse
|
|
2
|
Sakita M, Isobe W, Nonaka K, Murakami S, Miyachi R, Sakane K, Sugimoto S, Yamaguchi A, Yamamoto K. Age‑related changes in endoplasmic reticulum stress response‑associated protein expression in rat tibial nerves. Biomed Rep 2025; 22:50. [PMID: 39882333 PMCID: PMC11775640 DOI: 10.3892/br.2025.1928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/13/2025] [Indexed: 01/31/2025] Open
Abstract
In age-related peripheral neurodegeneration, changes in the promotion or inhibition of endoplasmic reticulum (ER) stress response related to the ubiquitin-proteasome degradation system (UPS), autophagy and apoptosis signaling factors during aging remain unclear. In the present study, the expression of ER stress response signaling-related protein factors was examined in tibial nerves during aging in rats. Tibial nerves were extracted from continuously housed rats at 20, 50, 70, 90 and 105 weeks of age. Expression of factors associated with ER stress-related degradation, including X-box binding protein 1 (XBP1s), eukaryotic translation initiation factor 2 subunit 1 (eIF2α), Beclin-1 (Becn1), and Caspase-3 (Casp3); ER stress-related repair, including binding immunoglobulin protein [also known as 78 kDa glucose-regulated protein (BiP/GRP78)], protein disulfide isomerase (PDI), brain-derived neurotrophic factor (BDNF) and the inflammatory cytokine IL6, was assessed by western blotting of tibial nerves from rats in each age group. Expression of XBP1s and Becn1, which promote UPS and autophagy, decreased significantly after 50 weeks of age. However, expression of eIF2α and Casp3, which inhibit new protein biosynthesis and promote apoptosis, increased significantly after 50 weeks. Expression of BiP/GRP78 and PDI, which are refolding factors for denatured proteins, showed a significant decrease after 50 (or 70) weeks of age. The expression of BDNF, a ligand protein for the repair cascade, showed a significant increase after 70 weeks of age, while that of IL6 increased significantly after 50 weeks of age. These results indicate that ER stress-related degradation (UPS and autophagy) and refolding repair functions are reduced in rat tibial nerves after 50 weeks, followed by enhanced apoptosis and inflammation. These findings shed light on the progression of age-related peripheral neurodegeneration in rats.
Collapse
Affiliation(s)
- Masahiro Sakita
- Department of Physical Therapy, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| | - Wataru Isobe
- Department of Physical Therapy, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
- Department of Rehabilitation, Mitsubishi Kyoto Hospital, Kyoto 615-8087, Japan
| | - Koji Nonaka
- Department of Rehabilitation, Faculty of Health Care Sciences, Naragakuen University, Nara 631-0003, Japan
| | - Shinichiro Murakami
- Department of Physical Therapy, Faculty of Health Care Sciences, Himeji-Dokkyo University, Himeji, Hyogo 670-0896, Japan
| | - Ryo Miyachi
- Department of Physical Therapy, Faculty of Health Care Sciences, Hokuriku University, Kanazawa, Ishikawa 920-1154, Japan
| | - Kento Sakane
- Department of Physical Therapy, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| | - Saki Sugimoto
- Department of Physical Therapy, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| | - Airi Yamaguchi
- Department of Physical Therapy, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| | - Koki Yamamoto
- Department of Physical Therapy, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| |
Collapse
|
|
3
|
Zobeydi AM, Mousavi Namavar SN, Sadeghi Shahdani M, Choobineh S, Kordi MR, Rakhshan K. Mitigating doxorubicin-induced hepatotoxicity in male rats: The role of aerobic interval training and curcumin supplementation in reducing oxidative stress, endoplasmic reticulum stress and apoptosis. Sci Rep 2025; 15:6604. [PMID: 39994295 PMCID: PMC11850886 DOI: 10.1038/s41598-025-91133-6] [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: 12/13/2024] [Accepted: 02/18/2025] [Indexed: 02/26/2025] Open
Abstract
Doxorubicin (DOXO) is a powerful anthracycline chemotherapeutic drug, but its clinical usage has been limited by its deleterious effects on different organs, particularly hepatotoxicity. The aim of this study was to establish the combined effects of aerobic interval training (AIT) and curcumin supplementation on mitigating oxidative damage and endoplasmic reticulum (ER) stress-mediated apoptosis in a rat model of DOXO-induced hepatotoxicity. Fifty-six male Sprague-Dawley rats were randomly split into six groups: control (CON), vehicle, doxorubicin (Dox), doxorubicin + curcumin (Dox-C), doxorubicin + AIT (Dox-A), and doxorubicin + curcumin + AIT (Dox-AC). DOXO was intraperitoneally injected weekly (4 mg/kg/week) for five weeks. Curcumin supplementation (100 mg/kg/day) and AIT (4 min at 80-90% of VO2max intermitted by 3 min of active rest at 65-75% of VO2max) were conducted five times a week for six weeks. Finally, the hepatic tissue and blood samples were collected to assess histopathological changes, liver damage biomarkers, and the protein expression of oxidative stress, ER stress, and apoptosis markers. Tissue sections revealed that AIT and curcumin supplementation significantly improved hepatotoxicity induced by DOXO, as evidenced by the positive effects on histopathological alterations and serum markers of hepatic damage (P < 0.05). Both curcumin and AIT significantly reduced DOXO-triggered oxidative damage, ER stress, and apoptosis (P < 0.05), with the latter showing slightly higher effectiveness. Consequently, the combination of AIT with curcumin supplementation exhibits protective effects against chronic hepatotoxicity induced by DOXO, with AIT demonstrating relatively greater efficacy in increasing antioxidant capacity and reducing ER stress and apoptosis.
Collapse
Affiliation(s)
- Amir Mohammad Zobeydi
- Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran.
| | | | - Maryam Sadeghi Shahdani
- Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran
| | - Siroos Choobineh
- Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran.
| | - Mohammad Reza Kordi
- Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran
| | - Kamran Rakhshan
- Department of Medical Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
4
|
İlhan İ, Asci H, Ozmen O, Buyukbayram Hİ, Arlıoglu M, Kurtbolat O. The renoprotective effects of cannabidiol on lipopolysaccharide-induced systemic inflammation model of rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1841-1851. [PMID: 39180672 DOI: 10.1007/s00210-024-03391-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 08/16/2024] [Indexed: 08/26/2024]
Abstract
Sepsis-induced renal damage poses a significant threat, necessitating effective therapeutic strategies. Cannabidiol (CBD) has beneficial effects on tissues and their functions by exhibiting antioxidant and anti-inflammatory effects. This study investigates the potential protective effects of CBD in mitigating lipopolysaccharide (LPS)-induced renal injury in Wistar Albino rats. Thirty-two Wistar Albino rats were categorized into control, LPS (5 mg/kg i.p.), LPS + CBD, and CBD (5 mg/kg i.p.) groups. After the experiment, samples were collected for biochemical, genetic, histopathological, and immunohistochemical analyses. Oxidative stress markers as total oxidant status (TOS) and total antioxidant status (TAS), oxidative stress index (OSI), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), immune staining as tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), caspase-3, gene expressions as nuclear factor erythroid 2-related factor 2 (NRF2), C/EBP homologous protein (CHOP), caspase-9, glucose-regulating protein 78 (GRP78), B-cell leukemia/lymphoma 2 (Bcl2), and tissue histology have been examined. The LPS-exposed group exhibited significant renal abnormalities, mitigated by CBD intervention in the LPS + CBD group. CBD reduced immunoexpression scores for TNF-α, caspase-3, and IL-10. Biochemically, CBD induced a positive shift in the oxidative balance, increasing TAS, SOD, and GPx, while decreasing TOS, OSI, and MDA levels. Genetic analyses highlighted CBD's regulatory impact on NRF2, CHOP, caspase-9, GRP78, and Bcl2, providing molecular insights into its protective role against LPS-induced renal damage. This study underscores CBD as a promising protective agent against sepsis-induced renal damage. Our findings could provide valuable insights into potential therapeutic avenues for addressing renal complications in sepsis.
Collapse
Affiliation(s)
- İlter İlhan
- Department of Biochemistry, Faculty of Medicine, Suleyman Demirel University, Isparta, 32200, Turkey.
| | - Halil Asci
- Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Ozlem Ozmen
- Department of Pathology, Faculty of Veterinary, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| | - Halil İbrahim Buyukbayram
- Department of Biochemistry, Faculty of Medicine, Suleyman Demirel University, Isparta, 32200, Turkey
| | - Melih Arlıoglu
- Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Okan Kurtbolat
- Department of Pharmacology, Institute of Medicine, Suleyman Demirel University, Isparta, Turkey
| |
Collapse
|
|
5
|
Wang L, Qu Z, Xu Y, Yu G, Liu X, Wang M, An S, Yin X, Na R, Hao Y. Insecticide chlorfenapyr confers induced toxicity in human cells through mitochondria-dependent pathways of apoptosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 289:117502. [PMID: 39657379 DOI: 10.1016/j.ecoenv.2024.117502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 12/12/2024]
Abstract
Pesticides are always used in the environment, the unexpected effects of pesticides on the environment and non-target organisms need to be continuously studied. Insecticide chlorfenapyr (Chl) is widely used in agriculture and also recommended for public health use (e.g., providing protection from malaria). Here we study toxic effects of Chl on human alveolar carcinoma cells (A549) and human normal liver cells (L02) in vitro. Chl's ability to induce DNA damage and apoptosis in human cells was confirmed through alkaline comet assay, immunofluorescence assay, and flow cytometric analysis. Further research showed that Chl induced mitochondrial damage (the collapse of mitochondrial membrane potential and the opening of mitochondrial permeability transition pore) with up-regulated expression of Bax/Bcl-2 leads to the release of cytochrome c from mitochondria which in turn activated the apoptotic pathway. Meanwhile, the key protein PARP is cleaved during apoptosis, resulting in the inhibition of DNA damage repair. In short, human A549 and L02 cells exposed to Chl were experiencing DNA damage and apoptosis linked to mitochondria. The results of this study supply theoretical understanding of Chl's toxicity on human cells, and can attract attention on the potential threat of insecticide Chl to human health.
Collapse
Affiliation(s)
- Longfei Wang
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Zheng Qu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China
| | - Yifan Xu
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Guangqing Yu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Xiangyang Liu
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Meizi Wang
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Shiheng An
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Xinming Yin
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Risong Na
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China
| | - Youwu Hao
- National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China.
| |
Collapse
|
|
6
|
Tang L, Guo X, Wen S, Duan Z, Zhong X, Liang M, Liao Y. Oxidative and Endoplasmic Reticulum Stress Mediate Testicular Injury in a Rat Model of Varicocele. Reprod Sci 2024:10.1007/s43032-024-01749-8. [PMID: 39638967 DOI: 10.1007/s43032-024-01749-8] [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: 08/05/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024]
Abstract
Evidence of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) have been increasingly reported in varicocele (VCL)-affected testes. However, the mechanisms by which oxidative stress (OS) and ER stress contribute to male infertility in VCL remain unclear. In this study, male Sprague-Dawley rats were divided into a control group, which underwent sham surgery, and a VCL group, in which VCL was surgically induced. Eight weeks postoperatively, the VCL group exhibited significant testicular damage and sperm abnormalities. Western blot analysis revealed upregulation of ER stress-related proteins and downstream apoptotic markers in the VCL group. For further investigation, we developed an in vitro oxidative stress model using GC-2 cells treated with 400 µM hydrogen peroxide (H2O2) for 12 h. Cells were also treated with either an ER stress inducer or inhibitor. We found that treatment with H2O2 and the ER stress inducer significantly reduced GC-2 cell viability and increased reactive oxygen species (ROS) production, ER stress, and apoptosis. Conversely, treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated these effects. Our findings suggest a strong association between VCL-induced redox imbalance and ER stress-related injury driven by the UPR in this rat model. Furthermore, 4-PBA effectively reduced germ cell damage induced by ROS-mediated ER stress, offering potential therapeutic insights for treating VCL-related infertility.
Collapse
Affiliation(s)
- Leming Tang
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
- Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
| | - Xinran Guo
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
| | - Shuman Wen
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
| | - Zhangyu Duan
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
| | - Xuansheng Zhong
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
| | - Meng Liang
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
- Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China
| | - Yaping Liao
- School of Life Sciences, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China.
- Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, 233000, China.
| |
Collapse
|
|
7
|
Abhirami N, Ayyappan JP. Cardioprotective effect of Robinin ameliorates Endoplasmic Reticulum Stress and Apoptosis in H9c2 cells. Cell Biochem Biophys 2024; 82:3681-3694. [PMID: 39095567 DOI: 10.1007/s12013-024-01456-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2024] [Indexed: 08/04/2024]
Abstract
Robinin is one of the glycosyloxyflavones that has been less explored for its therapeutic application, especially in the field of CVD. Herein, we explored the cardioprotective efficacy of Robinin by using H2O2 and Doxorubicin (DOX) - treated H9c2 cells as an in vitro model. H2O2 and DOX treatment resulted in severe cellular damage to the cardiomyocytes, which was followed by apoptosis. Apoptosis and nuclear morphology were analysed through Hoechst 33342 and AO/EB staining. qPCR was employed to detect the expression of apoptosis as well as ERS-related markers. Reactive oxygen species (ROS) generation was observed using DCFH-DA staining and FACS analysis. Signaling pathways involved were analysed using Western blot. Robinin pre-treatment considerably decreased the apoptotic rate by boosting the endogenous anti-oxidative activity and lowering the activity of Malonaldehyde and Lactate dehydrogenase enzyme. Robinin also inhibited the generation of ROS. Robinin reduced the expression of ERS-associated genes and proteins, thereby decreasing apoptosis-related proteins. Upon comparing the cardioprotective effect of Robinin with a known cardioprotective agent Dexrazoxane (DEX) it was revealed that DEX has more cardioprotective effect against DOX than H2O2-induced stress, while Robinin showed a significant protective effect against both H2O2 and DOX induced stress.
Collapse
Affiliation(s)
- N Abhirami
- Translational Nanomedicine and Lifestyle Disease Research Laboratory, Department of Biochemistry, University of Kerala, Kariavattom campus, Thiruvananthapuram, 695034, Kerala, India
| | - Janeesh Plakkal Ayyappan
- Translational Nanomedicine and Lifestyle Disease Research Laboratory, Department of Biochemistry, University of Kerala, Kariavattom campus, Thiruvananthapuram, 695034, Kerala, India.
- Centre for Advanced Cancer Research, Department of Biochemistry, University of Kerala, Kariavattom campus, Thiruvananthapuram, 695034, Kerala, India.
| |
Collapse
|
|
8
|
Colina SE, Williman MM, Tizzano MA, Serena MS, Echeverría MG, Metz GE. Morbillivirus Canis Infection Induces Activation of Three Branches of Unfolded Protein Response, MAPK and Apoptosis. Viruses 2024; 16:1846. [PMID: 39772156 PMCID: PMC11680218 DOI: 10.3390/v16121846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/19/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025] Open
Abstract
Morbillivirus canis, commonly named Canine distemper virus (CDV), is a morbillivirus implicated in several signs in the Canidae family. In dogs (Canis lupus familiaris), common signs of infection include conjunctivitis, digital hyperkeratosis and neuropathologies. Even with vaccination, the canine distemper disease persists worldwide so the molecular pathways implicated in the infection processes have been an interesting and promising area in new therapeutic drugs research in recent years. It is known that in the process of virus infection, the endoplasmic reticulum (ER) loses its homeostasis, inducing stress and the subsequent unfolded protein response or UPR in which three ER-trans-membrane proteins are implicated: PERK, IRE1 and ATF6. Moreover, in prolonged ER stress, the apoptosis is induced through the CHOP, as a final step of viral infection. Cell culture and molecular techniques such as RT-qPCR and RT-PCR were used in the present study. We demonstrate the activation in vitro of the three UPR pathways after infection with an attenuated strain of CDV. Also, the implication of a MAPK pathway through the p38 protein and the apoptotic CHOP was demonstrated to contribute to the process of infection. Even more, our study suggested that CDV replication occurs in a PERK-dependent manner.
Collapse
Affiliation(s)
- Santiago Emanuel Colina
- Laboratorio de Virología, Centro de Microbiología Básica y Aplicada (CEMIBA), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata CP 1900, Buenos Aires, Argentina; (S.E.C.); (M.M.W.); (M.A.T.); (M.S.S.); (M.G.E.)
- Consejo Nacional de Investigaciones Cientìficas y Técnicas (CONICET), CCT-La Plata, La Plata CP 1900, Buenos Aires, Argentina
| | - Macarena Marta Williman
- Laboratorio de Virología, Centro de Microbiología Básica y Aplicada (CEMIBA), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata CP 1900, Buenos Aires, Argentina; (S.E.C.); (M.M.W.); (M.A.T.); (M.S.S.); (M.G.E.)
- Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Godoy Cruz 2370, Ciudad Autónoma de Buenos Aires (CABA) C1425FQD, Argentina
| | - Marco Antonio Tizzano
- Laboratorio de Virología, Centro de Microbiología Básica y Aplicada (CEMIBA), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata CP 1900, Buenos Aires, Argentina; (S.E.C.); (M.M.W.); (M.A.T.); (M.S.S.); (M.G.E.)
| | - María Soledad Serena
- Laboratorio de Virología, Centro de Microbiología Básica y Aplicada (CEMIBA), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata CP 1900, Buenos Aires, Argentina; (S.E.C.); (M.M.W.); (M.A.T.); (M.S.S.); (M.G.E.)
- Consejo Nacional de Investigaciones Cientìficas y Técnicas (CONICET), CCT-La Plata, La Plata CP 1900, Buenos Aires, Argentina
| | - María Gabriela Echeverría
- Laboratorio de Virología, Centro de Microbiología Básica y Aplicada (CEMIBA), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata CP 1900, Buenos Aires, Argentina; (S.E.C.); (M.M.W.); (M.A.T.); (M.S.S.); (M.G.E.)
- Consejo Nacional de Investigaciones Cientìficas y Técnicas (CONICET), CCT-La Plata, La Plata CP 1900, Buenos Aires, Argentina
| | - Germán Ernesto Metz
- Laboratorio de Virología, Centro de Microbiología Básica y Aplicada (CEMIBA), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata CP 1900, Buenos Aires, Argentina; (S.E.C.); (M.M.W.); (M.A.T.); (M.S.S.); (M.G.E.)
- Consejo Nacional de Investigaciones Cientìficas y Técnicas (CONICET), CCT-La Plata, La Plata CP 1900, Buenos Aires, Argentina
| |
Collapse
|
|
9
|
Mustafa M, Ahmad R, Tantry IQ, Ahmad W, Siddiqui S, Alam M, Abbas K, Moinuddin, Hassan MI, Habib S, Islam S. Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications. Cells 2024; 13:1838. [PMID: 39594587 PMCID: PMC11592877 DOI: 10.3390/cells13221838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/16/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Cell survival and death are intricately governed by apoptosis, a meticulously controlled programmed cell death. Apoptosis is vital in facilitating embryonic development and maintaining tissue homeostasis and immunological functioning. It is a complex interplay of intrinsic and extrinsic signaling pathways that ultimately converges on executing the apoptotic program. The extrinsic pathway is initiated by the binding of death ligands such as TNF-α and Fas to their respective receptors on the cell surface. In contrast, the intrinsic pathway leads to increased permeability of the outer mitochondrial membrane and the release of apoptogenic factors like cytochrome c, which is regulated by the Bcl-2 family of proteins. Once activated, these pathways lead to a cascade of biochemical events, including caspase activation, DNA fragmentation, and the dismantling of cellular components. Dysregulation of apoptosis is implicated in various disorders, such as cancer, autoimmune diseases, neurodegenerative disorders, and cardiovascular diseases. This article focuses on elucidating the molecular mechanisms underlying apoptosis regulation, to develop targeted therapeutic strategies. Modulating apoptotic pathways holds immense potential in cancer treatment, where promoting apoptosis in malignant cells could lead to tumor regression. This article demonstrates the therapeutic potential of targeting apoptosis, providing options for treating cancer and neurological illnesses. The safety and effectiveness of apoptosis-targeting drugs are being assessed in ongoing preclinical and clinical trials (phase I-III), opening the door for more effective therapeutic approaches and better patient outcomes.
Collapse
Affiliation(s)
- Mohd Mustafa
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India; (M.M.); (R.A.); (S.S.); (M.)
| | - Rizwan Ahmad
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India; (M.M.); (R.A.); (S.S.); (M.)
| | - Irfan Qadir Tantry
- Department of Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar 190006, India;
| | - Waleem Ahmad
- Department of Medicine, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India;
| | - Sana Siddiqui
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India; (M.M.); (R.A.); (S.S.); (M.)
| | - Mudassir Alam
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202001, India; (M.A.); (K.A.)
| | - Kashif Abbas
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202001, India; (M.A.); (K.A.)
| | - Moinuddin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India; (M.M.); (R.A.); (S.S.); (M.)
| | - Md. Imtaiyaz Hassan
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India;
| | - Safia Habib
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India; (M.M.); (R.A.); (S.S.); (M.)
| | - Sidra Islam
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| |
Collapse
|
|
10
|
Moghadam RK, Daraei A, Haddadi M, Mardi A, Karamali N, Rezaiemanesh A. Casting Light on the Janus-Faced HMG-CoA Reductase Degradation Protein 1: A Comprehensive Review of Its Dualistic Impact on Apoptosis in Various Diseases. Mol Neurobiol 2024; 61:6842-6863. [PMID: 38356096 DOI: 10.1007/s12035-024-03994-z] [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: 12/05/2023] [Accepted: 01/29/2024] [Indexed: 02/16/2024]
Abstract
Nowadays, it is well recognized that apoptosis, as a highly regulated cellular process, plays a crucial role in various biological processes, such as cell differentiation. Dysregulation of apoptosis is strongly implicated in the pathophysiology of numerous disorders, making it essential to comprehend its underlying mechanisms. One key factor that has garnered significant attention in the regulation of apoptotic pathways is HMG-CoA reductase degradation protein 1, also known as HRD1. HRD1 is an E3 ubiquitin ligase located in the endoplasmic reticulum (ER) membrane. Its primary role involves maintaining the quality control of ER proteins by facilitating the ER-associated degradation (ERAD) pathway. During ER stress, HRD1 aids in the elimination of misfolded proteins that accumulate within the ER. Therefore, HRD1 plays a pivotal role in the regulation of apoptotic pathways and maintenance of ER protein quality control. By targeting specific protein substrates and affecting apoptosis-related pathways, HRD1 could be an exclusive therapeutic target in different disorders. Dysregulation of HRD1-mediated processes contributes significantly to the pathophysiology of various diseases. The purpose of this review is to assess the effect of HRD1 on the pathways related to apoptosis in various diseases from a therapeutic perspective.
Collapse
Affiliation(s)
- Reihaneh Khaleghi Moghadam
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, PO-Box: 6714869914, Kermanshah, Iran
| | - Arshia Daraei
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, PO-Box: 6714869914, Kermanshah, Iran
| | - Maryam Haddadi
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, PO-Box: 6714869914, Kermanshah, Iran
| | - Amirhossein Mardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Karamali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, PO-Box: 6714869914, Kermanshah, Iran.
| |
Collapse
|
|
11
|
Svandova E, Vesela B, Janeckova E, Chai Y, Matalova E. Exploring caspase functions in mouse models. Apoptosis 2024; 29:938-966. [PMID: 38824481 PMCID: PMC11263464 DOI: 10.1007/s10495-024-01976-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2024] [Indexed: 06/03/2024]
Abstract
Caspases are enzymes with protease activity. Despite being known for more than three decades, caspase investigation still yields surprising and fascinating information. Initially associated with cell death and inflammation, their functions have gradually been revealed to extend beyond, targeting pathways such as cell proliferation, migration, and differentiation. These processes are also associated with disease mechanisms, positioning caspases as potential targets for numerous pathologies including inflammatory, neurological, metabolic, or oncological conditions. While in vitro studies play a crucial role in elucidating molecular pathways, they lack the context of the body's complexity. Therefore, laboratory animals are an indispensable part of successfully understanding and applying caspase networks. This paper aims to summarize and discuss recent knowledge, understanding, and challenges in caspase knock-out mice.
Collapse
Affiliation(s)
- Eva Svandova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetic, Brno, Czech Republic.
| | - Barbora Vesela
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetic, Brno, Czech Republic
| | - Eva Janeckova
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, USA
| | - Eva Matalova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetic, Brno, Czech Republic
- Department of Physiology, University of Veterinary Sciences, Brno, Czech Republic
| |
Collapse
|
|
12
|
Unal O, Erzurumlu Y, Asci H, Gunduru Acar B, Bedir M, Ozmen O. Nebivolol protects the liver against lipopolysaccharide-induced oxidative stress, inflammation, and endoplasmic reticulum-related apoptosis through Chop and Bip/GRP78 signaling. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5899-5907. [PMID: 38353687 PMCID: PMC11329546 DOI: 10.1007/s00210-024-02990-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 01/29/2024] [Indexed: 08/18/2024]
Abstract
This study aimed to examine the protective role of nebivolol (NEB) on liver tissue against the lipopolysaccharide (LPS)-induced sepsis model in rats by targeting endoplasmic reticulum (ER) stress-related binding immunoglobulin protein (Bip), CCAAT-enhancer-binding protein homologous protein (Chop) signaling pathways. Four groups, each comprising eight rats, were established: control, LPS, LPS + NEB, and NEB. Biochemical analyses included total oxidant status (TOS), serum aspartate transaminase (AST), and alanine aminotransferase (ALT) levels. Additionally, genetic assessments involved Chop and Bip/GRP78 mRNA expression levels, while histopathological examinations were conducted. Immunohistochemistry was used to determine interleukin-1 beta (IL-1 β) and caspase-3 levels. The LPS group exhibited significantly higher AST, ALT, oxidative stress index, and TOS levels compared to the control group. Moreover, the LPS group demonstrated markedly increased Chop and Bip/GRP78 mRNA expression compared to the control group. Immunohistochemical analysis of the LPS group revealed significant upregulation in IL-1β and caspase-3 expressions compared to the control group. Additionally, the LPS group showed significant hyperemia, mild hemorrhage, and inflammatory cell infiltrations. Comparatively, the LPS+NEB group exhibited a reversal of these alterations when compared to the LPS group. Collectively, our findings, suggest that NEB holds promise as a treatment in conditions where oxidative damage, inflammation, and ER stress-related apoptosis play significant roles in the pathogenesis.
Collapse
Affiliation(s)
- Onur Unal
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey.
| | - Yalcin Erzurumlu
- Department of Biochemistry, Faculty of Pharmacy, Suleyman Demirel University, Isparta, Turkey
| | - Halil Asci
- Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Berivan Gunduru Acar
- Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Mehmet Bedir
- Department of Biochemistry, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Ozlem Ozmen
- Department of Pathology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| |
Collapse
|
|
13
|
Hu Y, Wang X, Niu Y, He K, Tang M. Application of quantum dots in brain diseases and their neurotoxic mechanism. NANOSCALE ADVANCES 2024; 6:3733-3746. [PMID: 39050959 PMCID: PMC11265591 DOI: 10.1039/d4na00028e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 06/01/2024] [Indexed: 07/27/2024]
Abstract
The early-stage diagnosis and therapy of brain diseases pose a persistent challenge in the field of biomedicine. Quantum dots (QDs), nano-luminescent materials known for their small size and fluorescence imaging capabilities, present promising capabilities for diagnosing, monitoring, and treating brain diseases. Although some investigations about QDs have been conducted in clinical trials, the concerns about the toxicity of QDs have continued. In addition, the lack of effective toxicity evaluation methods and systems and the difference between in vivo and in vitro toxicity evaluation hinder QDs application. The primary objective of this paper is to introduce the neurotoxic effects and mechanisms attributable to QDs. First, we elucidate the utilization of QDs in brain disorders. Second, we sketch out three pathways through which QDs traverse into brain tissue. Ultimately, expound upon the adverse consequences of QDs on the brain and the mechanism of neurotoxicity in depth. Finally, we provide a comprehensive summary and outlook on the potential development of quantum dots in neurotoxicity and the difficulties to be overcome.
Collapse
Affiliation(s)
- Yuanyuan Hu
- Key Laboratory of Environmental Medicine & Engineering, Ministry of Education, School of Public Health, Southeast University Nanjing Jiangsu 210009 China
| | - Xiaoli Wang
- Key Laboratory of Environmental Medicine & Engineering, Ministry of Education, School of Public Health, Southeast University Nanjing Jiangsu 210009 China
| | - Yiru Niu
- Key Laboratory of Environmental Medicine & Engineering, Ministry of Education, School of Public Health, Southeast University Nanjing Jiangsu 210009 China
| | - Keyu He
- Blood Transfusion Department, Clinical Laboratory, Zhongda Hospital, Southeast University Nanjing Jiangsu 210009 China
| | - Meng Tang
- Key Laboratory of Environmental Medicine & Engineering, Ministry of Education, School of Public Health, Southeast University Nanjing Jiangsu 210009 China
| |
Collapse
|
|
14
|
Wu TJ, Jing X, Teng M, Pritchard KA, Day BW, Naylor S, Teng RJ. Role of Myeloperoxidase, Oxidative Stress, and Inflammation in Bronchopulmonary Dysplasia. Antioxidants (Basel) 2024; 13:889. [PMID: 39199135 PMCID: PMC11351552 DOI: 10.3390/antiox13080889] [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: 07/02/2024] [Revised: 07/19/2024] [Accepted: 07/21/2024] [Indexed: 09/01/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a lung complication of premature births. The leading causes of BPD are oxidative stress (OS) from oxygen treatment, infection or inflammation, and mechanical ventilation. OS activates alveolar myeloid cells with subsequent myeloperoxidase (MPO)-mediated OS. Premature human neonates lack sufficient antioxidative capacity and are susceptible to OS. Unopposed OS elicits inflammation, endoplasmic reticulum (ER) stress, and cellular senescence, culminating in a BPD phenotype. Poor nutrition, patent ductus arteriosus, and infection further aggravate OS. BPD survivors frequently suffer from reactive airway disease, neurodevelopmental deficits, and inadequate exercise performance and are prone to developing early-onset chronic obstructive pulmonary disease. Rats and mice are commonly used to study BPD, as they are born at the saccular stage, comparable to human neonates at 22-36 weeks of gestation. The alveolar stage in rats and mice starts at the postnatal age of 5 days. Because of their well-established antioxidative capacities, a higher oxygen concentration (hyperoxia, HOX) is required to elicit OS lung damage in rats and mice. Neutrophil infiltration and ER stress occur shortly after HOX, while cellular senescence is seen later. Studies have shown that MPO plays a critical role in the process. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), a reversible MPO inhibitor, attenuates BPD effectively. In contrast, the irreversible MPO inhibitor-AZD4831-failed to provide similar efficacy. Interestingly, KYC cannot offer its effectiveness without the existence of MPO. We review the mechanisms by which this anti-MPO agent attenuates BPD.
Collapse
Affiliation(s)
- Tzong-Jin Wu
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (X.J.); (M.T.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Xigang Jing
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (X.J.); (M.T.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Michelle Teng
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (X.J.); (M.T.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Kirkwood A. Pritchard
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
- Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
| | - Billy W. Day
- ReNeuroGen LLC, 2160 San Fernando Dr, Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Stephen Naylor
- ReNeuroGen LLC, 2160 San Fernando Dr, Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Ru-Jeng Teng
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (X.J.); (M.T.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| |
Collapse
|
|
15
|
Gu X, Li F, Che X, Wei X, Li P. HDAC4 represses ER stress induced chondrocyte apoptosis by inhibiting ATF4 and attenuates cartilage degeneration in an osteoarthritis rat model. BMC Musculoskelet Disord 2024; 25:467. [PMID: 38879481 PMCID: PMC11179397 DOI: 10.1186/s12891-024-07578-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 06/07/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND The present study evaluated whether the lack of histone deacetylase 4 (HDAC4) increases endoplasmic reticulum stress-induced chondrocyte apoptosis by releasing activating transcription factor 4 (ATF4) in human osteoarthritis (OA) cartilage degeneration. METHODS Articular cartilage from the tibial plateau was obtained from patients with OA during total knee replacement. Cartilage extracted from severely damaged regions was classified as degraded cartilage, and cartilage extracted from a relatively smooth region was classified as preserved cartilage. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was used to detect chondrocyte apoptosis. HDAC4, ATF4, and C/EBP homologous protein (CHOP) expression levels were measured using immunohistochemistry staining and real-time quantitative PCR. Chondrocytes were transfected with HDAC4 or HDAC4 siRNA for 24 h and stimulated with 300 µM H2O2 for 12 h. The chondrocyte apoptosis was measured using flow cytometry. ATF4, CHOP, and caspase 12 expression levels were measured using real-time quantitative PCR and western blotting. Male Sprague-Dawley rats (n = 15) were randomly divided into three groups and transduced with different vectors: ACLT + Ad-GFP, ACLT + Ad-HDAC4-GFP, and sham + Ad-GFP. All rats received intra-articular injections 48 h after the operation and every three weeks thereafter. Cartilage damage was assessed using Safranin O staining and quantified using the Osteoarthritis Research Society International score. ATF4, CHOP, and collagen II expression were detected using immunohistochemistry, and chondrocyte apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. RESULTS The chondrocyte apoptosis was higher in degraded cartilage than in preserved cartilage. HDAC4 expression was lower in degraded cartilage than in preserved cartilage. ATF4 and CHOP expression was increased in degraded cartilage. Upregulation of HDAC4 in chondrocytes decreased the expression of ATF4, while the expression of ATF4 was increased after downregulation of HDAC4. Upregulation of HDAC4 decreased the chondrocyte apoptosis under endoplasmic reticulum stress, and chondrocyte apoptosis was increased after downregulation of HDAC4. In a rat anterior cruciate ligament transection OA model, adenovirus-mediated transduction of HDAC4 was administered by intra-articular injection. We detected a stronger Safranin O staining with lower Osteoarthritis Research Society International scores, lower ATF4 and CHOP production, stronger collagen II expression, and lower chondrocyte apoptosis in rats treated with Ad-HDAC4. CONCLUSION The lack of HDAC4 expression partially contributes to increased ATF4, CHOP, and endoplasmic reticulum stress-induced chondrocyte apoptosis in OA pathogenesis. HDAC4 attenuates cartilage damage by repressing ATF4-CHOP signaling-induced chondrocyte apoptosis in a rat model of OA.
Collapse
Affiliation(s)
- Xiaodong Gu
- Department of Orthopaedics, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences,Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi Province, 030032, People's Republic of China
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi Province, 030001, People's Republic of China
| | - Fei Li
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, 030001, People's Republic of China
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi Province, 030001, People's Republic of China
| | - Xianda Che
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, 030001, People's Republic of China
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi Province, 030001, People's Republic of China
| | - Xiaochun Wei
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, 030001, People's Republic of China
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi Province, 030001, People's Republic of China
| | - Pengcui Li
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, 030001, People's Republic of China.
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi Province, 030001, People's Republic of China.
| |
Collapse
|
|
16
|
Li CC, Tsai BCK, Annseles Rajula S, Hsu CH, Chen MC, Kuo CH, Yeh CM, Hsieh DJY, Kuo WW, Huang CY. Tannic Acid Impedes the Proliferation of Bladder Cancer Cells by Elevating Mitochondrial Pathways of Apoptosis. Cell Biochem Biophys 2024; 82:1325-1333. [PMID: 38809348 DOI: 10.1007/s12013-024-01286-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2024] [Indexed: 05/30/2024]
Abstract
Bladder cancer stands as a prevailing neoplasm among men globally, distinguished for its pronounced malignancy attributed to invasiveness and metastatic proclivity. Tannic acid (TA), an organic compound in many plants, has garnered recent attention for its discernible anti-mutagenic attributes. This investigation endeavored to scrutinize the repercussions of TA on grade II bladder cancer, with a concerted focus on unraveling its anti-cancer mechanisms. The cytotoxic effects of TA on grade II bladder cancer cells were investigated using multiple techniques, including MTT assay, flow cytometry, TUNEL assay, and western blot. Our findings revealed that elevated concentrations of TA induced cytotoxic effects in grade II bladder cancer cells. Both flow cytometry and the TUNEL assay substantiated the dose-dependent capacity of TA to prompt apoptosis. Western blot analysis corroborated that TA treatment in bladder cancer cells resulted in the upregulation of cleaved caspase-3 expression and PARP. Furthermore, heightened TA dosage elicited an augmentation in the expression of pro-apoptotic proteins, namely Bax and Bak, alongside a reduction in the expression of the anti-apoptotic protein Bcl-2 within bladder cancer cells. This study confirms TA as a potential anticancer agent, demonstrably diminishing the viability of bladder cancer cells. TA exerts cytotoxicity through the activation of mitochondrial apoptotic pathways. Specifically, TA initiates the cleavage of PARP and caspase-3, concurrently augmenting the expression of pro-apoptotic proteins to facilitate apoptosis. Collectively, the present study indicates that TA effectively impedes the proliferation of bladder cancer cells by instigating apoptosis through the intrinsic mitochondrial pathway.
Collapse
Affiliation(s)
- Chi-Cheng Li
- Center of Stem Cell and Precision Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Bruce Chi-Kang Tsai
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Selvaraj Annseles Rajula
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Chiung-Hung Hsu
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Ming-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Hua Kuo
- Department of Sports Sciences, University of Taipei, Taipei, Taiwan
- Laboratory of Exercise Biochemistry, University of Taipei, Tianmu Campus, Taipei, Taiwan
- Department of Kinesiology and Health Science, College of William and Mary, Williamsburg, VA, USA
- School of Physical Education and Sports Science, Soochow University, Suzhou, China
| | - Chung-Min Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Dennis Jine-Yuan Hsieh
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan.
- Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, Taiwan.
- School of Pharmacy, China Medical University, Taichung, Taiwan.
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan.
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
| |
Collapse
|
|
17
|
Okan A, Demir N, Doğanyiğit Z. Linagliptin in combination with insulin suppresses apoptotic unfolded protein response in ovaries exposed to type 1 diabetes. Cell Biochem Funct 2024; 42:e3898. [PMID: 38088568 DOI: 10.1002/cbf.3898] [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: 07/25/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 03/14/2024]
Abstract
Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum (ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar-lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ER stress in type 1 diabetic mouse ovaries. Eighty-four Balb/C 6-week-old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro-survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism-dependent survival in ovaries with type 1 diabetes.
Collapse
Affiliation(s)
- Aslı Okan
- Department of Histology and Embryology, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| | - Necdet Demir
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Züleyha Doğanyiğit
- Department of Histology and Embryology, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| |
Collapse
|
|
18
|
Arruebarrena MA, Hawe CT, Lee YM, Branco RC. Mechanisms of Cadmium Neurotoxicity. Int J Mol Sci 2023; 24:16558. [PMID: 38068881 PMCID: PMC10706630 DOI: 10.3390/ijms242316558] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/17/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023] Open
Abstract
Cadmium is a heavy metal that increasingly contaminates food and drink products. Once ingested, cadmium exerts toxic effects that pose a significant threat to human health. The nervous system is particularly vulnerable to prolonged, low-dose cadmium exposure. This review article provides an overview of cadmium's primary mechanisms of neurotoxicity. Cadmium gains entry into the nervous system via zinc and calcium transporters, altering the homeostasis for these metal ions. Once within the nervous system, cadmium disrupts mitochondrial respiration by decreasing ATP synthesis and increasing the production of reactive oxygen species. Cadmium also impairs normal neurotransmission by increasing neurotransmitter release asynchronicity and disrupting neurotransmitter signaling proteins. Cadmium furthermore impairs the blood-brain barrier and alters the regulation of glycogen metabolism. Together, these mechanisms represent multiple sites of biochemical perturbation that result in cumulative nervous system damage which can increase the risk for neurological and neurodegenerative disorders. Understanding the way by which cadmium exerts its effects is critical for developing effective treatment and prevention strategies against cadmium-induced neurotoxic insult.
Collapse
Affiliation(s)
- Madelyn A. Arruebarrena
- Neuroscience and Behavior Program, University of Notre Dame, Notre Dame, IN 46556, USA; (M.A.A.); (Y.M.L.)
| | - Calvin T. Hawe
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA;
| | - Young Min Lee
- Neuroscience and Behavior Program, University of Notre Dame, Notre Dame, IN 46556, USA; (M.A.A.); (Y.M.L.)
| | - Rachel C. Branco
- Neuroscience and Behavior Program, University of Notre Dame, Notre Dame, IN 46556, USA; (M.A.A.); (Y.M.L.)
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA;
| |
Collapse
|
|
19
|
Zhang X, Liu B, Lal K, Liu H, Tran M, Zhou M, Ezugwu C, Gao X, Dang T, Au ML, Brown E, Wu H, Liao Y. Antioxidant System and Endoplasmic Reticulum Stress in Cataracts. Cell Mol Neurobiol 2023; 43:4041-4058. [PMID: 37874455 PMCID: PMC10842247 DOI: 10.1007/s10571-023-01427-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 10/14/2023] [Indexed: 10/25/2023]
Abstract
The primary underlying contributor for cataract, a leading cause of vision impairment and blindness worldwide, is oxidative stress. Oxidative stress triggers protein damage, cell apoptosis, and subsequent cataract formation. The nuclear factor-erythroid 2-related factor 2 (Nrf2) serves as a principal redox transcriptional factor in the lens, offering a line of defense against oxidative stress. In response to oxidative challenges, Nrf2 dissociates from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), moves to the nucleus, and binds to the antioxidant response element (ARE) to activate the Nrf2-dependent antioxidant system. In parallel, oxidative stress also induces endoplasmic reticulum stress (ERS). Reactive oxygen species (ROS), generated during oxidative stress, can directly damage proteins, causing them to misfold. Initially, the unfolded protein response (UPR) activates to mitigate excessive misfolded proteins. Yet, under persistent or severe stress, the failure to rectify protein misfolding leads to an accumulation of these aberrant proteins, pushing the UPR towards an apoptotic pathway, further contributing to cataractogenesis. Importantly, there is a dynamic interaction between the Nrf2 antioxidant system and the ERS/UPR mechanism in the lens. This interplay, where ERS/UPR can modulate Nrf2 expression and vice versa, holds potential therapeutic implications for cataract prevention and treatment. This review explores the intricate crosstalk between these systems, aiming to illuminate strategies for future advancements in cataract prevention and intervention. The Nrf2-dependent antioxidant system communicates and cross-talks with the ERS/UPR pathway. Both mechanisms are proposed to play pivotal roles in the onset of cataract formation.
Collapse
Affiliation(s)
- Xi Zhang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Bingqing Liu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Kevin Lal
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Haihua Liu
- Peking University First Hospital, Beijing, China
| | - Myhoa Tran
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Manyu Zhou
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Chimdindu Ezugwu
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Xin Gao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Terry Dang
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - My-Lien Au
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Erica Brown
- School of Medicine, Texas Christian University and University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Hongli Wu
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA.
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA.
| | - Yan Liao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| |
Collapse
|
|
20
|
Tepebaşı MY, Büyükbayram Hİ, Özmen Ö, Taşan Ş, Selçuk E. Dexpanthenol ameliorates doxorubicin-induced lung injury by regulating endoplasmic reticulum stress and apoptosis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1837-1845. [PMID: 37074393 DOI: 10.1007/s00210-023-02497-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 04/13/2023] [Indexed: 04/20/2023]
Abstract
Doxorubicin (DOX), which is used as a chemotherapeutic agent in the treatment of tumors, has limited use due to its toxicity in various organs and tissues. One of the organs where DOX has a toxic effect is the lung. DOX shows this effect by increasing oxidative stress, inflammation, and apoptosis. Dexpanthenol (DEX), a homologue of pantothenic acid, has anti-inflammatory, antioxidant, and anti-apoptotic properties. Therefore, the purpose of our investigation was to explore how DEX could counteract the harmful effects of DOX on the lungs. Thirty-two rats were used in the study, and 4 groups were formed (control, DOX, DOX + DEX, and DEX). In these groups, parameters of inflammation, ER stress, apoptosis, and oxidative stress were evaluated by immunohistochemistry, RT-qPCR, and spectrophotometric methods. In addition, lung tissue was evaluated histopathologically in the groups. While CHOP/GADD153, caspase-12, caspase-9, and Bax gene expressions increased in the DOX group, Bcl-2 gene expression levels significantly decreased. In addition, changes in Bax and Bcl-2 were supported immunohistochemically. There was a significant increase in oxidative stress parameters and a significant decrease in antioxidant levels. In addition, an increase in inflammatory marker (TNF-α and IL-10) levels was determined. There was a decrease in CHOP/GADD153, caspase-12, caspase-9, and Bax gene expressions and an increase in Bcl-2 gene expression in the DEX-treated group. In addition, it was determined that there was a decrease in oxidative stress levels and inflammatory findings. The curative effect of DEX was supported by histopathological findings. As a result, it was experimentally determined that DEX has a healing effect on oxidative stress, ER stress, inflammation, and apoptosis in lung damage caused by DOX toxicity.
Collapse
Affiliation(s)
| | | | - Özlem Özmen
- Department of Pathology, University of Mehmet Akif Ersoy, Burdur, Turkey
| | - Şerife Taşan
- Department of Pathology, University of Mehmet Akif Ersoy, Burdur, Turkey
| | - Esma Selçuk
- Department of Medical Biology, University of Süleyman Demirel, Isparta, Turkey
| |
Collapse
|
|
21
|
Lv R, Liu X, Zhang Y, Dong N, Wang X, He Y, Yue H, Yin Q. Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome. Signal Transduct Target Ther 2023; 8:218. [PMID: 37230968 DOI: 10.1038/s41392-023-01496-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 05/27/2023] Open
Abstract
Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea. The prevalence of OSAS continues to rise worldwide, particularly in middle-aged and elderly individuals. The mechanism of upper airway collapse is incompletely understood but is associated with several factors, including obesity, craniofacial changes, altered muscle function in the upper airway, pharyngeal neuropathy, and fluid shifts to the neck. The main characteristics of OSAS are recurrent pauses in respiration, which lead to intermittent hypoxia (IH) and hypercapnia, accompanied by blood oxygen desaturation and arousal during sleep, which sharply increases the risk of several diseases. This paper first briefly describes the epidemiology, incidence, and pathophysiological mechanisms of OSAS. Next, the alterations in relevant signaling pathways induced by IH are systematically reviewed and discussed. For example, IH can induce gut microbiota (GM) dysbiosis, impair the intestinal barrier, and alter intestinal metabolites. These mechanisms ultimately lead to secondary oxidative stress, systemic inflammation, and sympathetic activation. We then summarize the effects of IH on disease pathogenesis, including cardiocerebrovascular disorders, neurological disorders, metabolic diseases, cancer, reproductive disorders, and COVID-19. Finally, different therapeutic strategies for OSAS caused by different causes are proposed. Multidisciplinary approaches and shared decision-making are necessary for the successful treatment of OSAS in the future, but more randomized controlled trials are needed for further evaluation to define what treatments are best for specific OSAS patients.
Collapse
Affiliation(s)
- Renjun Lv
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Xueying Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Yue Zhang
- Department of Geriatrics, the 2nd Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Na Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Xiao Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yao He
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Hongmei Yue
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
| | - Qingqing Yin
- Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
| |
Collapse
|
|
22
|
Le M, Li J, Zhang D, Yuan Y, Zhou C, He J, Huang J, Hu L, Luo T, Zheng L. The emerging role of lysine succinylation in ovarian aging. Reprod Biol Endocrinol 2023; 21:38. [PMID: 37081483 PMCID: PMC10116721 DOI: 10.1186/s12958-023-01088-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 04/04/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Ovarian aging is a process of decline in its reserve leading to ovary dysfunction and even reduced health quality in offspring. However, aging-related molecular pathways in the ovary remain obscure. Lysine succinylation (Ksuc), a newly post-translational modification (PTM), has been found to be broadly conserved in both eukaryotic and prokaryotic cells, and associated with multiple pathophysiological processes. There are no relevant reports revealing a link between the molecular mechanisms of ovarian aging and Ksuc. METHODS The level of Ksuc in ovaries of aged and premature ovarian insufficiency (POI) mice were detected by immunoblotting and immunohistochemical. To further explore the role of Ksuc in ovarian aging, using in vitro mouse ovary tissue culture and an in vivo mouse model with changed Ksuc level. RESULTS Increased Ksuc in ovaries of aged and POI mice and distribution of Ksuc in various types of mice ovarian cells and the high level of Ksuc in granulosa cells (GCs) were revealed. Histological assessments and hormone levels analyses showed that the high Ksuc level down-regulated the ovarian index and the anti-Müllerian hormone (AMH) and estrogen levels, and increased follicular atresia. Moreover, in the high Ksuc groups, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) intensities and the expression of Cleaved-caspase-3 increased and the expression of B-cell lymphoma-2 (Bcl-2) decreased together with positively-expressed P21, an aging-related marker. These results suggest that ovarian aging is likely associated with alteration in Ksuc. CONCLUSION The present study has identified Ksuc in mouse ovary and found that high Ksuc level most likely contributes to ovarian aging which is expected further investigation to provide new information for delaying physiological ovarian aging and treating pathological ovarian aging.
Collapse
Affiliation(s)
- Meiling Le
- School of Public Health and Basic Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jia Li
- School of Public Health and Basic Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Dalei Zhang
- School of Public Health and Basic Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yuan Yuan
- Basic Medical College and Institute of Life Science, Nanchang University, Nanchang, Jiangxi, 330031, China
| | - Chong Zhou
- School of Public Health and Basic Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jinxia He
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jian Huang
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Liaoliao Hu
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Tao Luo
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Basic Medical College and Institute of Life Science, Nanchang University, Nanchang, Jiangxi, 330031, China.
| | - Liping Zheng
- School of Public Health and Basic Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, Jiangxi, 330006, China.
| |
Collapse
|
|
23
|
Kim SH, Oh SH. Sodium arsenite-induced cytotoxicity is regulated by BNIP3L/Nix-mediated endoplasmic reticulum stress responses and CCPG1-mediated endoplasmic reticulum-phagy. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 99:104111. [PMID: 36925093 DOI: 10.1016/j.etap.2023.104111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 03/05/2023] [Accepted: 03/13/2023] [Indexed: 06/18/2023]
Abstract
We elucidated the BNIP3L/Nix and SQSTM1/p62 molecular mechanisms in sodium arsenite (NaAR)-induced cytotoxicity. Considerable changes in the morphology and adhesion of H460 cells were observed in response to varying NaAR concentrations. NaAR exposure induced DNA damage-mediated apoptosis and Nix accumulation via proteasome inhibition. Nix targets the endoplasmic reticulum (ER), inducing ER stress responses. p62 and Nix were colocalized and their expressions were inversely correlated. Autophagy inhibition upregulated Nix, p62, cell cycle progression gene 1 (CCPG1), heme oxygenase (HO)- 1, and calnexin expression. Nix knockdown decreased the NaAR-induced ER stress and microtubule-associated protein 1 A/1B light-chain 3 (LC3) B-II levels and increased the CCPG1 and calnexin levels. p62 knockdown upregulated Nix, LC3-II, and CCPG1 expressions and the ER stress responses, indicating that p62 regulates Nix levels. Nix downstream pathways were mitigated by Ca2+ chelators. We demonstrate the critical roles of Nix and p62 in ER stress and ER-phagy in response to NaAR.
Collapse
Affiliation(s)
- Sang-Hun Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759, South Korea
| | - Seon-Hee Oh
- School of Medicine, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759, South Korea.
| |
Collapse
|
|
24
|
Hack SJ, Beane WS, Tseng KAS. Biophysics at the edge of life and death: radical control of apoptotic mechanisms. FRONTIERS IN CELL DEATH 2023; 2:1147605. [PMID: 39897412 PMCID: PMC11784940 DOI: 10.3389/fceld.2023.1147605] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Recent studies have furthered our understanding of how dying and living cells interact in different physiological contexts, however the signaling that initiates and mediates apoptosis and apoptosis-induced proliferation are more complex than previously thought. One increasingly important area of study is the biophysical control of apoptosis. In addition to biochemical regulation, biophysical signals (including redox chemistry, bioelectric gradients, acoustic and magnetic stimuli) are also known yet understudied regulators of both cell death and apoptosis-induced proliferation. Mounting evidence suggests biophysical signals may be key targets for therapeutic interventions. This review highlights what is known about the role of biophysical signals in controlling cell death mechanisms during development, regeneration, and carcinogenesis. Since biophysical signals can be controlled spatiotemporally, bypassing the need for genetic manipulation, further investigation may lead to fine-tuned modulation of apoptotic pathways to direct desired therapeutic outcomes.
Collapse
Affiliation(s)
- Samantha J. Hack
- Western Michigan University, Department of Biological Sciences, Kalamazoo, MI, USA
| | - Wendy S. Beane
- Western Michigan University, Department of Biological Sciences, Kalamazoo, MI, USA
| | - Kelly Ai-Sun Tseng
- University of Nevada, Las Vegas, School of Life Sciences, Las Vegas, NV, USA
| |
Collapse
|
|
25
|
Wen S, Chen Y, Tang Y, Zhao Y, Liu S, You T, Xu H. Male reproductive toxicity of polystyrene microplastics: Study on the endoplasmic reticulum stress signaling pathway. Food Chem Toxicol 2023; 172:113577. [PMID: 36563925 DOI: 10.1016/j.fct.2022.113577] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 11/06/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Microplastics (MPs) have raised health concerns in public for its potential reproductive toxicity. In this study, we subjected the Kunming mice to 0.01, 0.1 and 1.0 mg/day polystyrene MPs (10 μm, PS-MPs) for 35 days, aiming to investigate the relevant male reproductive toxicity and latent molecular mechanism. The results showed the decreased sperm counts and motility, while the elevated sperm abnormality in PS-MPs-exposed mice. Testicular H&E staining displayed the vacuolization, atrophy, and even shedding of germ cells in seminiferous tubule. And the testosterone content in serum also decreased with PS-MPs treatment. Moreover, molecular analysis indicated that PS-MPs upregulated the expression trait factors for ERS (e.g., immunoglobulin-binding protein [BIP], inositol-requiring protein 1α [IRE1α], X-box-binding protein 1 splicing [XBP1s], Jun kinase [JNK], and the transcription of CCAAT/enhancer-binding protein (C/EBP) homologous protein [CHOP]) and downstream apoptotic modulator (e.g., Caspase-12, -9, and -3) in the testis. The steroidogenic acute regulatory protein (StAR), the testosterone synthetic initiator, was also downregulated. With the supplementation of ERS inhibitor, the MPs-induced testicular damage and decreased testosterone were improved to almost normal level. Overall, this study suggested that PS-MPs generate reproductive toxicity possibly via activating ERS and apoptosis signaling pathway.
Collapse
Affiliation(s)
- Siyue Wen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
| | - Yanbiao Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
| | - Yizhou Tang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
| | - Yu Zhao
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
| | - Shanji Liu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
| | - Tao You
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China.
| |
Collapse
|
|
26
|
Ye W, Dai M, Bian D, Zhu Q, Li X, Sun H, Li F, Wei J, Li B. Sublethal chlorantraniliprole exposure induces autophagy and apoptosis through disrupting calcium homeostasis in the silkworm Bombyx mori. INSECT MOLECULAR BIOLOGY 2023; 32:36-45. [PMID: 36093732 DOI: 10.1111/imb.12811] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 09/08/2022] [Indexed: 06/15/2023]
Abstract
The intensive application of chlorantraniliprole (CAP) leaves residues in the environment, posing a potential threat to non-target organisms. In the present study, we investigated the adverse effects of sublethal CAP exposure on Bombyx mori. Sublethal CAP (0.02 mg/L) was shown to induce the release of intracellular Ca2+ in BmN cells. Meanwhile, Ca2+ -dependent genes were induced in the midgut at 72 h after CAP (0.01 mg/L) exposure, and damaged mitochondria, autophagosomes, nuclear membrane rupture and condensed chromatin were observed. Moreover, the key genes in the oxidative phosphorylation pathway were significantly down-regulated. The transcript levels of autophagy-related genes ATG6 and ATG8 were significantly up-regulated, and the protein levels of LC3-II and ATG7 were significantly increased by 3.72- and 3.33-fold, respectively. Additionally, the transcript levels of the upstream genes in the apoptosis pathway (calpain and Apaf-1) were significantly up-regulated, the protein levels of the downstream gene caspase 3 and its cleaved form were significantly up-regulated by 1.97- and 4.55-fold, respectively, consistent with the elevated caspase 3 activity at 72 h. Collectively, these findings demonstrate that intracellular Ca2+ release induced by sublethal CAP inhibits oxidative phosphorylation pathway, which causes mitochondrial dysfunction, leading to autophagy and apoptosis in the midgut of B. mori.
Collapse
Affiliation(s)
- WenTao Ye
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
| | - MinLi Dai
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
| | - DanDan Bian
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
| | - QingYu Zhu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
| | - Xin Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
| | - HaiNa Sun
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
- Sericulture Institute of Soochow University, Soochow University, Suzhou, China
| | - FanChi Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
- Sericulture Institute of Soochow University, Soochow University, Suzhou, China
| | - Jing Wei
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
- Sericulture Institute of Soochow University, Soochow University, Suzhou, China
| | - Bing Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, China
- Sericulture Institute of Soochow University, Soochow University, Suzhou, China
| |
Collapse
|
|
27
|
Wang W, Guan J, Feng Y, Nie L, Xu Y, Xu H, Fu F. Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats. Front Nutr 2023; 9:1059660. [PMID: 36687698 PMCID: PMC9853403 DOI: 10.3389/fnut.2022.1059660] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/19/2022] [Indexed: 01/08/2023] Open
Abstract
Introduction Unintended intake of microplastic particles has been demonstrated to exert adverse health effects, however, studies on relevant nephrotoxicity in juvenile mammals are lacking. Methods Therefore, we investigated the potential nephrotoxicity of oral-exposed polystyrene microplastics (PSMPs) (1,000 nm, 2.0 mg/kg/d) for 28 days in juvenile rats. Levels of oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in kidneys were analyzed. Results and discussion Results revealed that PSMPs noticeably decreased the growth rate of bodyweight, and organ index of the kidney, cardiac, and ovary. The intestinal injury caused by PSMPs exposure was also observed, which was distinctly alleviated with N-acetyl-cysteine (NAC) and Salubrinal (Sal) treatment compared with the single PSMPs group. PSMPs caused histological lesions of the kidney via disrupting the serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1β, IL-6, and TNF-α. Furthermore, PSMPs exposure induced ER stress and inflammation presumably potentially mediated by oxidative stress in kidneys of rats. Eventually, PSMPs also promoted renal cells apoptosis, manifested as an obvious increase in the number of positive cells for the dUTP nick end labeling of Terminal deoxynucleotidyl transferase, which also can be confirmed by the elevated expression of genes associated with apoptosis Bcl-2, Bax, Caspase-12, Caspase-9, Caspase-3, and IHC score of Caspase-12 in the PSMPs group. Supplementation of NAC and Sal not only ameliorated the PSMPs-induced oxidative stress and ER stress but also the inflammation and apoptosis in the kidney. Collectively, this study suggested that PSMPs caused nephrotoxicity in juvenile rats potentially through oxidative damage and ER stress, which call for greater efforts to be taken on regulating the PSMPs ingestion in children.
Collapse
Affiliation(s)
- Wanzhen Wang
- The Second Affiliated Hospital of Nanchang University, Nanchang, China,State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Jiafu Guan
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yueying Feng
- The Second Affiliated Hospital of Nanchang University, Nanchang, China,State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Liju Nie
- Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Yuanyuan Xu
- The Second Affiliated Hospital of Nanchang University, Nanchang, China,State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China,*Correspondence: Hengyi Xu, ,
| | - Fen Fu
- The Second Affiliated Hospital of Nanchang University, Nanchang, China,Fen Fu,
| |
Collapse
|
|
28
|
Panagaki T, Randi EB, Szabo C, Hölscher C. Incretin Mimetics Restore the ER-Mitochondrial Axis and Switch Cell Fate Towards Survival in LUHMES Dopaminergic-Like Neurons: Implications for Novel Therapeutic Strategies in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2023; 13:1149-1174. [PMID: 37718851 PMCID: PMC10657688 DOI: 10.3233/jpd-230030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/25/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that afflicts more than 10 million people worldwide. Available therapeutic interventions do not stop disease progression. The etiopathogenesis of PD includes unbalanced calcium dynamics and chronic dysfunction of the axis of the endoplasmic reticulum (ER) and mitochondria that all can gradually favor protein aggregation and dopaminergic degeneration. OBJECTIVE In Lund Human Mesencephalic (LUHMES) dopaminergic-like neurons, we tested novel incretin mimetics under conditions of persistent, calcium-dependent ER stress. METHODS We assessed the pharmacological effects of Liraglutide-a glucagon-like peptide-1 (GLP-1) analog-and the dual incretin GLP-1/GIP agonist DA3-CH in the unfolded protein response (UPR), cell bioenergetics, mitochondrial biogenesis, macroautophagy, and intracellular signaling for cell fate in terminally differentiated LUHMES cells. Cells were co-stressed with the sarcoplasmic reticulum calcium ATPase (SERCA) inhibitor, thapsigargin. RESULTS We report that Liraglutide and DA3-CH analogs rescue the arrested oxidative phosphorylation and glycolysis. They mitigate the suppressed mitochondrial biogenesis and hyper-polarization of the mitochondrial membrane, all to re-establish normalcy of mitochondrial function under conditions of chronic ER stress. These effects correlate with a resolution of the UPR and the deficiency of components for autophagosome formation to ultimately halt the excessive synaptic and neuronal death. Notably, the dual incretin displayed a superior anti-apoptotic effect, when compared to Liraglutide. CONCLUSIONS The results confirm the protective effects of incretin signaling in ER and mitochondrial stress for neuronal degeneration management and further explain the incretin-derived effects observed in PD patients.
Collapse
Affiliation(s)
- Theodora Panagaki
- Faculty of Science & Medicine, University of Fribourg, Fribourg, Switzerland
| | - Elisa B. Randi
- Faculty of Science & Medicine, University of Fribourg, Fribourg, Switzerland
| | - Csaba Szabo
- Faculty of Science & Medicine, University of Fribourg, Fribourg, Switzerland
| | - Christian Hölscher
- Research & Experimental Center, Henan University of Chinese Medicine, Zhengzhou, China
| |
Collapse
|
|
29
|
Vestuto V, Di Sarno V, Musella S, Di Dona G, Moltedo O, Gomez-Monterrey IM, Bertamino A, Ostacolo C, Campiglia P, Ciaglia T. New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors? Int J Mol Sci 2022; 24:185. [PMID: 36613628 PMCID: PMC9820239 DOI: 10.3390/ijms24010185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling events termed unfolded protein response (UPR), activated as adaptative response to mitigate the ER stress condition. In this regard, calcium levels play a pivotal role in ER homeostasis and therefore in cell fate regulation since calcium signaling is implicated in a plethora of physiological processes, but also in disease conditions such as neurodegeneration, cancer and metabolic disorders. A large body of emerging evidence highlighted the functional role of TRP channels and their ability to promote cell survival or death depending on endoplasmic reticulum stress resolution, making them an attractive target. Thus, in this review we focused on the TRP channels' correlation to UPR-mediated ER stress in disease pathogenesis, providing an overview of their implication in the activation of this cellular response.
Collapse
Affiliation(s)
- Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Veronica Di Sarno
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Simona Musella
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Giorgio Di Dona
- Pineta Grande Hospital, Via Domiziana, km 30/00, 81030 Castel Volturno, CE, Italy
| | - Ornella Moltedo
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | | | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Carmine Ostacolo
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
- European Biomedical Research Institute of Salerno, Via S. De Renzi 50, 84125 Salerno, SA, Italy
| | - Tania Ciaglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| |
Collapse
|
|
30
|
Mao W, Chen J, Wang Y, Fang Y, Wu H, He P. Combination of carboplatin and photodynamic therapy with 9-hydroxypheophorbide ɑ enhances mitochondrial and endoplasmic reticulum apoptotic effect in AMC-HN-3 laryngeal cancer cells. Photodiagnosis Photodyn Ther 2022; 40:103135. [PMID: 36272509 DOI: 10.1016/j.pdpdt.2022.103135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Previously, we demonstrated that the combined mode of carboplatin (CBDCA) and photodynamic therapy (PDT) based on 9-hydroxypheophorbide (9-HPbD) enhanced cytotoxicity and apoptosis on AMC-HN-3 laryngeal cancer cells. The present study aimed to investigate anti-tumor effect of the combined therapy in vivo and the potential role of reactive oxygen species (ROS) in these enhanced apoptotic pathways initiated by the combined therapy in AMC-HN-3 cells. METHODS Mitochondrial membrane potential (MMP) and intracellular Ca2+were detected under confocal microscopy. Various apoptotic pathways were detected by western blots. In vivo study with the combined regimen was also performed on AMC-HN-3 cells-xenograft nude mice. RESULTS In vitro study showed that the combined treatment could decrease the level of MMP, increase intracellular Ca2+ and AIF translocation, and activate the expression of caspase-12. Mechanismly, the augmented apoptotic effect was mediated by ROS. The synergistic antitumor effect was also observed in vivo. CONCLUSIONS The mechanism of CBDCA and 9-HPbD-PDT combination involves ROS-mediated mitochondrial and endoplasmic reticulum apoptosis pathways. This combination may be a promising treatment strategy for laryngeal cancer.
Collapse
Affiliation(s)
- Wenjing Mao
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Jian Chen
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Yimiao Wang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Yi Fang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Haitao Wu
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.
| | - Peijie He
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
31
|
Yu Y, Yang A, Yu G, Wang H. Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives. Biomolecules 2022; 12:1637. [PMID: 36358987 PMCID: PMC9687722 DOI: 10.3390/biom12111637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 09/08/2024] Open
Abstract
The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, apoptosis, and autophagy. Numerous studies have linked ER stress and UPR to the progression of chronic obstructive pulmonary disease (COPD). This review focuses on the mechanisms of other cellular processes triggered by UPR and summarizes drug intervention strategies targeting the UPR pathway in COPD to explore new therapeutic approaches and preventive measures for COPD.
Collapse
Affiliation(s)
| | | | - Ganggang Yu
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Haoyan Wang
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| |
Collapse
|
|
32
|
Docosahexaenoic Acid Counteracts the Hypoxic-Induced Inflammatory and Metabolic Alterations in 3T3-L1 Adipocytes. Nutrients 2022; 14:nu14214600. [PMID: 36364860 PMCID: PMC9659308 DOI: 10.3390/nu14214600] [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: 09/07/2022] [Revised: 10/15/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Background: Hypoxia is caused by the excessive expansion of the white adipose tissue (AT) and is associated with obesity-related conditions such as insulin resistance, inflammation, and oxidative stress. Docosahexaenoic acid (DHA) is an omega-3 fatty acid reported to have beneficial health effects. However, the effects of DHA in AT against hypoxia-induced immune-metabolic perturbations in adipocytes exposed to low O2 tension are not well known. Consequently, this study aimed to evaluate the impact of DHA on markers of inflammation, metabolism, apoptosis, and oxidative stress in 3T3-L1 cell adipocytes exposed to low O2 tension (1% O2) induced hypoxia. Methods: The apoptosis and reactive oxygen species (ROS) rates were evaluated. Metabolic parameters such as lactate, FFA, glycerol release, glucose uptake, and ATP content were assessed by a fluorometer. The expression of HIF-1, GLUT1 and the secretion of adipocytokines such as leptin, adiponectin, and pro-inflammatory markers was evaluated. Results: DHA-treated hypoxic cells showed significantly decreased basal free fatty acid release, lactate production, and enhanced glucose consumption. In addition, DHA-treatment of hypoxic cells caused a significant reduction in the apoptosis rate and ROS production with decreased lipid peroxidation. Moreover, DHA-treatment of hypoxic cells caused a decreased secretion of pro-inflammatory markers (IL-6, MCP-1) and leptin and increased adiponectin secretion compared with hypoxic cells. Furthermore, DHA-treatment of hypoxic cells caused significant reductions in the expression of genes related to hypoxia (HIF-1, HIF-2), anaerobic metabolism (GLUT1 and Ldha), ATP production (ANT2), and fat metabolism (FASN and PPARY). Conclusion: This study suggests that DHA can exert potential anti-obesity effects by reducing the secretion of inflammatory adipokines, oxidative stress, lipolysis, and apoptosis.
Collapse
|
|
33
|
Spinal Stroke: Outcome Attenuation by Erythropoietin and Carbamylated Erythropoietin and Its Prediction by Sphingosine-1-Phosphate Serum Levels in Mice. Int J Mol Sci 2022; 23:ijms23179558. [PMID: 36076955 PMCID: PMC9455176 DOI: 10.3390/ijms23179558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Spinal strokes may be associated with tremendous spinal cord injury. Erythropoietin (EPO) improves the neurological outcome of animals after spinal cord ischemia (SCI) and its effects on ischemia-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are considered possible molecular mechanisms. Furthermore, sphingosin-1-phosphate (S1P) is suggested to correlate with SCI. In this study, the effect of recombinant human EPO (rhEPO) and carbamylated EPO (cEPO-Fc) on the outcome of mice after SCI and a prognostic value of S1P were investigated. SCI was induced in 12-month-old male mice by thoracic aortal cross-clamping after administration of rhEPO, cEPO-Fc, or a control. The locomotory behavior of mice was evaluated by the Basso mouse scale and S1P serum levels were measured by liquid chromatography-tandem mass spectrometry. The spinal cord was examined histologically and the expressions of key UPR proteins (ATF6, PERK, and IRE1a, caspase-12) were analyzed utilizing immunohistochemistry and real-time quantitative polymerase chain reaction. RhEPO and cEPO-Fc significantly improved outcomes after SCI. The expression of caspase-12 significantly increased in the control group within the first 24 h of reperfusion. Animals with better locomotory behavior had significantly higher serum levels of S1P. Our data indicate that rhEPO and cEPO-Fc have protective effects on the clinical outcome and neuronal tissue of mice after SCI and that the ER is involved in the molecular mechanisms. Moreover, serum S1P may predict the severity of impairment after SCI.
Collapse
|
|
34
|
Hakiminia B, Alikiaii B, Khorvash F, Mousavi S. Oxidative stress and mitochondrial dysfunction following traumatic brain injury: From mechanistic view to targeted therapeutic opportunities. Fundam Clin Pharmacol 2022; 36:612-662. [PMID: 35118714 DOI: 10.1111/fcp.12767] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/15/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
Traumatic brain injury (TBI) is one of the most prevalent causes of permanent physical and cognitive disabilities. TBI pathology results from primary insults and a multi-mechanistic biochemical process, termed as secondary brain injury. Currently, there are no pharmacological agents for definitive treatment of patients with TBI. This article is presented with the purpose of reviewing molecular mechanisms of TBI pathology, as well as potential strategies and agents against pathological pathways. In this review article, materials were obtained by searching PubMed, Scopus, Elsevier, Web of Science, and Google Scholar. This search was considered without time limitation. Evidence indicates that oxidative stress and mitochondrial dysfunction are two key mediators of the secondary injury cascade in TBI pathology. TBI-induced oxidative damage results in the structural and functional impairments of cellular and subcellular components, such as mitochondria. Impairments of mitochondrial electron transfer chain and mitochondrial membrane potential result in a vicious cycle of free radical formation and cell apoptosis. The results of some preclinical and clinical studies, evaluating mitochondria-targeted therapies, such as mitochondria-targeted antioxidants and compounds with pleiotropic effects after TBI, are promising. As a proposed strategy in recent years, mitochondria-targeted multipotential therapy is a new hope, waiting to be confirmed. Moreover, based on the available findings, biologics, such as stem cell-based therapy and transplantation of mitochondria are novel potential strategies for the treatment of TBI; however, more studies are needed to clearly confirm the safety and efficacy of these strategies.
Collapse
Affiliation(s)
- Bahareh Hakiminia
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babak Alikiaii
- Department of Anesthesiology and Intensive Care, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fariborz Khorvash
- Department of Neurology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sarah Mousavi
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
35
|
Biological Effects and Mechanisms of Caspases in Early Brain Injury after Subarachnoid Hemorrhage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3345637. [PMID: 35847583 PMCID: PMC9277153 DOI: 10.1155/2022/3345637] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022]
Abstract
Caspases are an evolutionarily conserved family of proteases responsible for mediating and initiating cell death signals. In the past, the dysregulated activation of caspases was reported to play diverse but equally essential roles in neurodegenerative diseases, such as brain injury and neuroinflammatory diseases. A subarachnoid hemorrhage (SAH) is a traumatic event that is either immediately lethal or induces a high risk of stroke and neurological deficits. Currently, the prognosis of SAH after treatment is not ideal. Early brain injury (EBI) is considered one of the main factors contributing to the poor prognosis of SAH. The mechanisms of EBI are complex and associated with oxidative stress, neuroinflammation, blood-brain barrier disruption, and cell death. Based on mounting evidence, caspases are involved in neuronal apoptosis or death, endothelial cell apoptosis, and increased inflammatory cytokine-induced by apoptosis, pyroptosis, and necroptosis in the initial stages after SAH. Caspases can simultaneously mediate multiple death modes and regulate each other. Caspase inhibitors (including XIAP, VX-765, and Z-VAD-FMK) play an essential role in ameliorating EBI after SAH. In this review, we explore the related pathways mediated by caspases and their reciprocal regulation patterns after SAH. Furthermore, we focus on the extensive crosstalk of caspases as a potential area of research on therapeutic strategies for treating EBI after SAH.
Collapse
|
|
36
|
Caspase-mediated regulation of the distinct signaling pathways and mechanisms in neuronal survival. Int Immunopharmacol 2022; 110:108951. [PMID: 35717837 DOI: 10.1016/j.intimp.2022.108951] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 02/06/2023]
Abstract
Caspases are intimately associated with altering various signaling pathways, resulting in programmed cell death or apoptosis. Apoptosis is necessary for the normal homeostasis of cells and their development. The untoward activation of apoptotic pathways indirectly or directly results in pathologies of various diseases. Identifying different caspases in apoptotic pathways directed the research to develop caspase inhibitors as therapeutic agents. However, no drug is available in the market that targets caspase inhibition and produces a therapeutic effect. Here, we will shed light on the role of caspases in the number of neuronal disorders and neurodegenerative diseases. The article reviews the findings about the activation of various upstream mechanisms associated with caspases in neurodegenerative disorders along with the recent progress in the generation of caspase inhibitors and the challenge faced in their development as therapeutic agents for neurological indications.
Collapse
|
|
37
|
Chukai Y, Ito G, Konno M, Sakata Y, Ozaki T. Mitochondrial calpain-5 truncates caspase-4 during endoplasmic reticulum stress. Biochem Biophys Res Commun 2022; 608:156-162. [DOI: 10.1016/j.bbrc.2022.03.156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/06/2023]
|
|
38
|
Hamada S, Takata T, Yamada K, Yamamoto M, Mae Y, Iyama T, Ikeda S, Kanda T, Sugihara T, Isomoto H. Steatosis is involved in the progression of kidney disease in a high-fat-diet-induced non-alcoholic steatohepatitis mouse model. PLoS One 2022; 17:e0265461. [PMID: 35294499 PMCID: PMC8926260 DOI: 10.1371/journal.pone.0265461] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/02/2022] [Indexed: 01/03/2023] Open
Abstract
Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health issues associated with the metabolic syndrome. Although NASH is a known risk factor of CKD, the mechanisms linking these two diseases remain poorly understood. We aimed to investigate alterations in the kidney complicated with dyslipidemia in an established NASH mouse model. Male C57BL6/J mice were fed with control diet or high-fat diet (HFD), containing 40% fat, 22% fructose, and 2% cholesterol for 16 weeks. Metabolic characteristics, histological changes in the kidney, endoplasmic reticulum (ER) stress, apoptosis, and fibrosis were evaluated by histological analysis, immunoblotting, and quantitative reverse transcription-polymerase chain reaction. Levels of serum aspartate aminotransferase, alanine aminotransferase, alkali-phosphatase, total cholesterol, and urinary albumin were significantly higher in mice fed with HFD. Remarkable steatosis, glomerular hypertrophy, and interstitial fibrosis were also shown in in the kidney by leveraging HFD. Furthermore, HFD increased the mRNA expression levels of Casp3, Tgfb1, and Nfe2l2 and the protein level of BiP. We observed the early changes of CKD and speculate that the underlying mechanisms that link CKD and NASH are the induction of ER stress and apoptosis. Further, we observed the activation of Nfe2l2 in the steatosis-induced CKD mouse model. This NASH model holds implications in investigating the mechanisms linking dyslipidemia and CKD.
Collapse
Affiliation(s)
- Shintaro Hamada
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Tomoaki Takata
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Kentaro Yamada
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Marie Yamamoto
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yukari Mae
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Takuji Iyama
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Suguru Ikeda
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Tsutomu Kanda
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Takaaki Sugihara
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| |
Collapse
|
|
39
|
Scutellarin Improves Type 2 Diabetic Cardiomyopathy by Regulating Cardiomyocyte Autophagy and Apoptosis. DISEASE MARKERS 2022; 2022:3058354. [PMID: 35571612 PMCID: PMC9106511 DOI: 10.1155/2022/3058354] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/15/2022] [Accepted: 03/07/2022] [Indexed: 11/17/2022]
Abstract
Diabetes cardiomyopathy has metabolic disorder and abnormality of cardiomyocytes, which is closely related to autophagy or apoptosis of cardiomyocytes. Scutellarin (SCU) is an important monomer extracted from Erigeron breviscapus (vant.) Hand.-Mazz. This study was conducted to investigate the function of SCU on apoptosis and autophagy of myocardial cells. We established a model of type 2 diabetic cardiomyopathy by high-fat and high-sugar diet. The results indicated that SCU downregulated blood glucose, total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels and upregulated high-density lipoprotein (HDL) level. In addition, SCU downregulated lactic dehydrogenase 1 (LDH1) and creatine kinase (CK) levels. Meanwhile, SCU improved the myocardium morphology and reduced myocardial apoptosis. Furthermore, SCU promoted the mRNA and protein expression of autophagy-related factors (Beclin-1 and LC3-II) and inhibited the mRNA and protein expression of apoptosis-related factors (caspase-3, caspase-8, caspase-9, caspase-12, Bax, and Cyt-C). In conclusion, SCU can promote autophagy signal pathway by upregulating the autophagy-related factors and inhibit the apoptotic signal pathway by downregulating apoptosis-related factors, thereby relieving type 2 diabetic cardiomyopathy (T2DC).
Collapse
|
|
40
|
Wang L, Liu Y, Zhang X, Ye Y, Xiong X, Zhang S, Gu L, Jian Z, Wang H. Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cerebral Ischemia/Reperfusion Injury. Front Cell Neurosci 2022; 16:864426. [PMID: 35602556 PMCID: PMC9114642 DOI: 10.3389/fncel.2022.864426] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is an acute cerebrovascular disease characterized by sudden interruption of blood flow in a certain part of the brain, leading to serious disability and death. At present, treatment methods for ischemic stroke are limited to thrombolysis or thrombus removal, but the treatment window is very narrow. However, recovery of cerebral blood circulation further causes cerebral ischemia/reperfusion injury (CIRI). The endoplasmic reticulum (ER) plays an important role in protein secretion, membrane protein folding, transportation, and maintenance of intracellular calcium homeostasis. Endoplasmic reticulum stress (ERS) plays a crucial role in cerebral ischemia pathophysiology. Mild ERS helps improve cell tolerance and restore cell homeostasis; however, excessive or long-term ERS causes apoptotic pathway activation. Specifically, the protein kinase R-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways are significantly activated following initiation of the unfolded protein response (UPR). CIRI-induced apoptosis leads to nerve cell death, which ultimately aggravates neurological deficits in patients. Therefore, it is necessary and important to comprehensively explore the mechanism of ERS in CIRI to identify methods for preserving brain cells and neuronal function after ischemia.
Collapse
Affiliation(s)
- Lei Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan Liu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingze Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shudi Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
- Zhihong Jian,
| | - Hongfa Wang
- Rehabilitation Medicine Center, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Hongfa Wang,
| |
Collapse
|
|
41
|
Gao H, He C, Hua R, Guo Y, Wang B, Liang C, Gao L, Shang H, Xu JD. Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases. Front Mol Biosci 2022; 9:817392. [PMID: 35402506 PMCID: PMC8988245 DOI: 10.3389/fmolb.2022.817392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 12/21/2022] Open
Abstract
The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.
Collapse
Affiliation(s)
- Han Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Chengwei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Rongxuan Hua
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yuexin Guo
- Department of Oral Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Boya Wang
- Undergraduate Student of 2018 Eight Program of Clinical Medicine, Peking University Health Science Center, Beijing, China
| | - Chen Liang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lei Gao
- Department of Biomedical Informatics, School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Hongwei Shang
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Jing-Dong Xu,
| |
Collapse
|
|
42
|
Banerjee DK, Seijo Lebrón A, Baksi K. Glycotherapy: A New Paradigm in Breast Cancer Research. Biomolecules 2022; 12:biom12040487. [PMID: 35454076 PMCID: PMC9026886 DOI: 10.3390/biom12040487] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/08/2022] [Accepted: 03/14/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is an ancient disease recognized first by the Egyptians as early as 1600 BC. The first cancer-causing gene in a chicken tumor virus was found in 1970. The United States signed the National Cancer Act in 1971, authorizing federal funding for cancer research. Irrespective of multi-disciplinary approaches, diverting a great deal of public and private resources, breast cancer remains at the forefront of human diseases, affecting as many as one in eight women during their lifetime. Because of overarching challenges and changes in the breast cancer landscape, five-year disease-free survival is no longer considered adequate. The absence of a cure, and the presence of drug resistance, severe side effects, and destruction of the patient’s quality of life, as well as the fact that therapy is often expensive, making it unaffordable to many, have created anxiety among patients, families, and friends. One of the reasons for the failure of cancer therapeutics is that the approaches do not consider cancer holistically. Characteristically, all breast cancer cells and their microenvironmental capillary endothelial cells express asparagine-linked (N-linked) glycoproteins with diverse structures. We tested a small biological molecule, Tunicamycin, that blocks a specific step of the protein N-glycosylation pathway in the endoplasmic reticulum (ER), i.e., the catalytic activity of N-acetylglusosaminyl 1-phosphate transferase (GPT). The outcome was overwhelmingly exciting. Tunicamycin quantitatively inhibits angiogenesis in vitro and in vivo, and inhibits the breast tumor progression of multiple subtypes in pre-clinical mouse models with “zero” toxicity. Mechanistic details support ER stress-induced unfolded protein response (upr) signaling as the cause for the apoptotic death of both cancer and the microvascular endothelial cells. Additionally, it interferes with Wnt signaling. We therefore conclude that Tunicamycin can be expected to supersede the current therapeutics to become a glycotherapy for treating breast cancer of all subtypes.
Collapse
Affiliation(s)
- Dipak K. Banerjee
- Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936-5067, USA;
- Correspondence:
| | - Arelis Seijo Lebrón
- Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936-5067, USA;
| | - Krishna Baksi
- Department of Anatomy and Cell Biology, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-3001, USA;
| |
Collapse
|
|
43
|
Zhang R, Liao W, Wu K, Hua L, Wu M, Li C, Cai F. Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway. Neurochem Int 2022; 154:105289. [PMID: 35074478 DOI: 10.1016/j.neuint.2022.105289] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 01/05/2022] [Accepted: 01/11/2022] [Indexed: 12/20/2022]
Abstract
Clinical and epidemiological studies indicate that diabetic cognitive impairment often occurs in diabetes mellitus patients. Matrine (Mat), an active component of Sophora flavescens Ait root extracts, has widely pharmacological activities including anti-tumor, anti-diabetes, cardioprotective and neuroprotective effects. The present study was designed to elucidate the possibly neuroprotective effects of Mat against diabetic spatial learning and memory impairment caused by high-fat diet and streptozotocin injection in mice. The results showed that Mat treatment significantly ameliorated fasting blood glucose level, impaired glucose tolerance, and lipid metabolism disorder in diabetic mice. In addition, diabetic mice exhibited spatial learning and memory impairment in the Morris water maze test, which could be attenuated by Mat treatment. Moreover, administration of Mat remarkably alleviated histological damage in diabetic hippocampus. Also, further investigations showed that Mat treatment abated endoplasmic reticulum stress induced hippocampal ultra-structure injury as evidenced by increasing the numbers of rough endoplasmic reticulum and mitochondria, as well as down-regulating endoplasmic reticulum stress related protein levels (GRP78, CHOP, ATF6 and Caspase-12). Furthermore, administration of Mat enhanced hippocampal protein expressions of PK2, PKR1 and PKR2, which decreased significantly in diabetic mice. Collectively, these findings suggested that Mat could ameliorate diabetes-induced spatial learning and memory impairment, possibly by alleviating ER stress, and partly through modulation of PK2/PKRs pathway.
Collapse
Affiliation(s)
- Ruyi Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China
| | - Wenli Liao
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China; Basic Medical School, Hubei University of Science and Technology, Xianning, 437100, China
| | - Ke Wu
- School of Health Sciences, Wuhan University, Wuhan, 430071, China
| | - Liangliang Hua
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China
| | - Mengyu Wu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China
| | - Cairong Li
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China; Clinical Medical School, Hubei University of Science and Technology, Xianning, 437100, China.
| | - Fei Cai
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China.
| |
Collapse
|
|
44
|
Huang K, Luo X, Zhong Y, Deng L, Feng J. New insights into the role of melatonin in diabetic cardiomyopathy. Pharmacol Res Perspect 2022; 10:e00904. [PMID: 35005848 PMCID: PMC8929360 DOI: 10.1002/prp2.904] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetic cardiovascular complications and impaired cardiac function are considered to be the main causes of death in diabetic patients worldwide, especially patients with type 2 diabetes mellitus (T2DM). An increasing number of studies have shown that melatonin, as the main product secreted by the pineal gland, plays a vital role in the occurrence and development of diabetes. Melatonin improves myocardial cell metabolism, reduces vascular endothelial cell death, reverses microcirculation disorders, reduces myocardial fibrosis, reduces oxidative and endoplasmic reticulum stress, regulates cell autophagy and apoptosis, and improves mitochondrial function, all of which are the characteristics of diabetic cardiomyopathy (DCM). This review focuses on the role of melatonin in DCM. We also discuss new molecular findings that might facilitate a better understanding of the underlying mechanism. Finally, we propose potential new therapeutic strategies for patients with T2DM.
Collapse
Affiliation(s)
- Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xianling Luo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Li Deng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| |
Collapse
|
|
45
|
Chanmanee T, Wongpun J, Tocharus C, Govitrapong P, Tocharus J. The effects of agomelatine on endoplasmic reticulum stress related to mitochondrial dysfunction in hippocampus of aging rat model. Chem Biol Interact 2022; 351:109703. [PMID: 34673010 DOI: 10.1016/j.cbi.2021.109703] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 10/03/2021] [Accepted: 10/10/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Agomelatine, a novel antidepressant, is a melatonin MT receptor agonist and serotonin 5HT2C receptor antagonist. In this study, agomelatine was used to investigate the molecular mechanisms of hippocampal aging associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and apoptosis, all of which led to short-term memory impairment. METHOD Hippocampal aging was induced in male Wistar rats by d-galactose (D-gal) intraperitoneal injection (100 mg/kg) for 14 weeks. During the last 4 weeks of D-gal treatment, rats were treated with agomelatine (40 mg/kg) or melatonin (10 mg/kg). At the end of the experiment, all rats were assessed for short-term memory by using the Morris water maze test. Subsequently, rats were sacrified and the hippocampus was removed from each rat for determination of reactive oxygen species (ROS), malondialdehyde (MDA), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays; and immunohistochemistry related to ER stress, mitochondrial dysfunction, and apoptosis. RESULTS Agomelatine suppressed the expression of the aging-related proteins P16 and receptor for advanced glycation endproducts (RAGE), the expression of NADPH oxidase (NOX) 2 and 4, and ROS production. This treatment also shifted the morphology of astrocytes and microglia toward homeostasis. Furthermore, agomelatine decreased inositol-requiring enzyme 1 (pIRE1), protein kinase R-like endoplasmic reticulum kinase (pPERK), and chaperone binding immunoglobulin protein (BiP), leading to suppression of ER stress markers C/EBP homologous protein (CHOP) and caspase-12. Agomelatine reduced Ca2+ from the ER and stabilized the mitochondrial membrane stability, which was denoted by the BCL2 Associated X (Bax)/B-cell lymphoma 2 (Bcl2) balance. Agomelatine decreased cleaved caspase-3 production and the Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL)-positive area, and glutamate excitotoxicity was prevented via suppression of N-methyl-d-aspartate (NMDA) receptor subunit expression. Agomelatine exhibited effects that were similar to melatonin. CONCLUSION Agomelatine improved neurodegeneration in a rat model of hippocampal aging by attenuating ROS production, ER stress, mitochondrial dysfunction, excitotoxicity, and apoptosis.
Collapse
Affiliation(s)
- Teera Chanmanee
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Graduate School, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Jittiporn Wongpun
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Piyarat Govitrapong
- Chulabhorn Graduate Institute, Kamphaeng Phet 6 Road, Lak Si, Bangkok, 10210, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Functional Food Research Center for Well-being, Chiang Mai University, Chiang Mai, 50200, Thailand.
| |
Collapse
|
|
46
|
Ovcjak A, Xiao A, Kim JS, Xu B, Szeto V, Turlova E, Abussaud A, Chen NH, Miller SP, Sun HS, Feng ZP. Ryanodine receptor inhibitor dantrolene reduces hypoxic-ischemic brain injury in neonatal mice. Exp Neurol 2022; 351:113985. [DOI: 10.1016/j.expneurol.2022.113985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 01/07/2022] [Accepted: 01/13/2022] [Indexed: 11/04/2022]
|
|
47
|
Sari I, Moch Rizal D, Afiyah Syarif R. The Effect of Chlorogenic Acid on Endoplasmic Reticulum Stress and Steroidogenesis in the Testes of Diabetic Rats: Study of mRNA Expressions of GRP78, XBP1s, 3β-HSD, and 17β-HSD. BIO WEB OF CONFERENCES 2022. [DOI: 10.1051/bioconf/20224901001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic endocrine metabolic disorder that can increase the incidence of infertility. Excessive production of reactive oxygen species (ROS) can trigger oxidative stress reactions and reduce antioxidant content. The increase of ROS can exert an impact on the endoplasmic reticulum (ER) stress conditions and inhibit the steroidogenesis of the testes. The objectives of the current study were to determine the effect of chlorogenic acid (CGA) as an antioxidant in reducing ER stress conditions (mRNA expressions of GRP78, XBP1s), and to increase steroidogenesis (mRNA expressions of 3β-HSD and 17β-HSD) in the testis of DM rats. A total of 24 rats were randomly divided into six groups, namely: control group, DM1.5 months, DM2 months, and DM group were treated with CGA with three different doses (12.5 mg/kgBW, 25 mg/kgBW, and 50 mg/kgBW), respectively. Testicular tissue was isolated for examination of GRP78, XBP1s, 3β-HSD, and 17β-HSD mRNA expressions using RT-PCR. In the CGA1 group, GRP78 mRNA expression level was lower than in the DM2 group and was statistically different (p=0.021). XBP1s mRNA expression in the CGA1 group was lower and significantly different when compared to the DM2 group (p=0.018). The mRNA expression of 3β -HSD in the CGA1 group was higher than that in the DM1.5 and DM2 groups, which were statistically significant with p=0.000 and p=0,008. The comparison of 17β - HSD mRNA expression in the CGA1 group was higher than the DM1,5 and DM2 groups with p=0.013 and p=0.012. Administration of CGA at a dose of 12.5 mg/kgBW can reduce ER stress conditions and increase testicular steroidogenesis in DM rat models. These results were seen based on low GRP78 and XBP1s mRNA expressions, and high 3β-HSD and 17β-HSD mRNA expressions after CGA administration.
Collapse
|
|
48
|
Armandeh M, Bameri B, Haghi-Aminjan H, Foroumadi R, Ataei M, Hassani S, Samadi M, Shayesteh MRH, Abdollahi M. A systematic review on the role of melatonin and its mechanisms on diabetes-related reproductive impairment in non-clinical studies. Front Endocrinol (Lausanne) 2022; 13:1022989. [PMID: 36303864 PMCID: PMC9592976 DOI: 10.3389/fendo.2022.1022989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/23/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Diabetes-induced reproductive complications can lead to subfertility and infertility, raising the need to protect reproductive organs. There are limited medications used to improve reproductive health in diabetic patients. Melatonin, mainly produced by the pineal gland, may improve diabetes-associated reproductive complications through various mechanisms and may be a preferred candidate to protect the reproductive system. The present review aims to elucidate the underlying mechanisms of melatonin's effect on the reproductive system adversely affected by diabetes mellitus (DM). METHODS A comprehensive systematic literature electronic search was done using the PRISMA guidelines. Web of Science, PubMed, Embase, and Scopus were searched for publications up to June 2022. Search terms were selected based on the study purpose and were explored in titles and abstracts. After screening, out of a total of 169 articles, 14 pertinent articles were included based on our inclusion and exclusion criteria. RESULTS The results of studies using rats and mice suggest that DM adversely affects reproductive tissues, including testes and epididymis, prostate, corpus cavernosum, and ovary leading to alterations in histological and biochemical parameters compared to the normal groups. Treatment with melatonin improves oxidative stress, blocks apoptosis induced by endoplasmic reticulum stress and caspase activation, reduces pro-inflammation cytokines, and enhances steroidogenesis. CONCLUSION Melatonin exerted a protective action on the impaired reproductive system in in-vivo and in-vitro models of DM. The topic has to be followed up in human pregnancy cases that will need more time to be collected and approved.
Collapse
Affiliation(s)
- Maryam Armandeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Toxicology & Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Behnaz Bameri
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Toxicology & Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- *Correspondence: Hamed Haghi-Aminjan, ; Mohammad Abdollahi, ;
| | - Roham Foroumadi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshid Ataei
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Toxicology & Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Shokoufeh Hassani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Toxicology & Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mahedeh Samadi
- Neuroscience Research Center, Iran University of Medical Science, Tehran, Iran
| | | | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Toxicology & Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Hamed Haghi-Aminjan, ; Mohammad Abdollahi, ;
| |
Collapse
|
|
49
|
Sharma M, Kumar V. Mosquito-larvicidal Binary (BinA/B) proteins for mosquito control programs —advancements, challenges, and possibilities. CURRENT RESEARCH IN INSECT SCIENCE 2022; 2:100028. [PMID: 36003274 PMCID: PMC9387486 DOI: 10.1016/j.cris.2021.100028] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 11/18/2022]
Abstract
Binary (BinAB) toxin is primarily responsible for the larvicidal action of the WHO recognized mosquito-larvicidal bacterium Lysinibacillus sphaericus. BinAB is a single receptor-specific toxin, active against larvae of Culex and Anopheles, but not Aedes aegypti. The target receptor in Culex is Cqm1 protein, a GPI-anchored amylomaltase located apically in the lipid-rafts of the larval-midgut epithelium. Interaction of the toxin components with the receptor is critical for the larvicidal activity of the toxin. Evidences support the pore formation model for BinAB toxin internalization and the role of toxin-glycan interactions in the endoplasmic reticulum in mediating larval death. Targeted R&D efforts are required to maintain the sustainability and improve efficacy of the eco-friendly BinAB proteins for efficient mosquito control interventions. The increasing global burden of mosquito-borne diseases require targeted, environmentally friendly, and sustainable approaches for effective vector control without endangering the non-target beneficial insect population. Biological interventions such as biopesticides, Wolbachia-mediated biological controls, or sterile insect techniques are used worldwide. Here we review Binary or BinAB toxin—the mosquito-larvicidal component of WHO-recognized Lysinibacillus sphaericus bacterium employed in mosquito control programs. Binary (BinAB) toxin is primarily responsible for the larvicidal effect of the bacterium. BinAB is a single-receptor-specific toxin and is effective against larvae of Culex and Anopheles, but not against Aedes aegypti. The receptor in Culex, the Cqm1 protein, has been extensively studied. It is a GPI-anchored amylomaltase and is located apically in the lipid rafts of the larval-midgut epithelium. The interaction of the toxin components with the receptor is crucial for the mosquito larvicidal activity of the BinAB toxin. Here we extend support for the pore formation model of BinAB toxin internalization and the role of toxin-glycan interactions in the endoplasmic reticulum in mediating larval death. BinAB is phylogenetically safe for humans, as Cqm1-like protein is not expected in the human proteome. This review aims to initiate targeted R&D efforts, such as applying fusion technologies (chimera of BinA, chemical modification of BinA), for efficient mosquito control interventions. In addition, the review also examines other areas such as bioremediation and cancer therapeutics, in which L. sphaericus is proving useful and showing potential for further development.
Collapse
Affiliation(s)
- Mahima Sharma
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra 400085, India
| | - Vinay Kumar
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra 400085, India
- Correspondence Author: Professor (Retired) Vinay Kumar, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra 400085, India
| |
Collapse
|
|
50
|
Piccialli I, Ciccone R, Secondo A, Boscia F, Tedeschi V, de Rosa V, Cepparulo P, Annunziato L, Pannaccione A. The Na +/Ca 2+ Exchanger 3 Is Functionally Coupled With the Na V1.6 Voltage-Gated Channel and Promotes an Endoplasmic Reticulum Ca 2+ Refilling in a Transgenic Model of Alzheimer's Disease. Front Pharmacol 2021; 12:775271. [PMID: 34955845 PMCID: PMC8692738 DOI: 10.3389/fphar.2021.775271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/22/2021] [Indexed: 01/15/2023] Open
Abstract
The remodelling of neuronal ionic homeostasis by altered channels and transporters is a critical feature of the Alzheimer's disease (AD) pathogenesis. Different reports converge on the concept that the Na+/Ca2+ exchanger (NCX), as one of the main regulators of Na+ and Ca2+ concentrations and signalling, could exert a neuroprotective role in AD. The activity of NCX has been found to be increased in AD brains, where it seemed to correlate with an increased neuronal survival. Moreover, the enhancement of the NCX3 currents (INCX) in primary neurons treated with the neurotoxic amyloid β 1-42 (Aβ1-42) oligomers prevented the endoplasmic reticulum (ER) stress and neuronal death. The present study has been designed to investigate any possible modulation of the INCX, the functional interaction between NCX and the NaV1.6 channel, and their impact on the Ca2+ homeostasis in a transgenic in vitro model of AD, the primary hippocampal neurons from the Tg2576 mouse, which overproduce the Aβ1-42 peptide. Electrophysiological studies, carried in the presence of siRNA and the isoform-selective NCX inhibitor KB-R7943, showed that the activity of a specific NCX isoform, NCX3, was upregulated in its reverse, Ca2+ influx mode of operation in the Tg2576 neurons. The enhanced NCX activity contributed, in turn, to increase the ER Ca2+ content, without affecting the cytosolic Ca2+ concentrations of the Tg2576 neurons. Interestingly, our experiments have also uncovered a functional coupling between NCX3 and the voltage-gated NaV1.6 channels. In particular, the increased NaV1.6 currents appeared to be responsible for the upregulation of the reverse mode of NCX3, since both TTX and the Streptomyces griseolus antibiotic anisomycin, by reducing the NaV1.6 currents, counteracted the increase of the INCX in the Tg2576 neurons. In agreement, our immunofluorescence analyses revealed that the NCX3/NaV1.6 co-expression was increased in the Tg2576 hippocampal neurons in comparison with the WT neurons. Collectively, these findings indicate that NCX3 might intervene in the Ca2+ remodelling occurring in the Tg2576 primary neurons thus emerging as a molecular target with a neuroprotective potential, and provide a new outcome of the NaV1.6 upregulation related to the modulation of the intracellular Ca2+ concentrations in AD neurons.
Collapse
Affiliation(s)
- Ilaria Piccialli
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Roselia Ciccone
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Agnese Secondo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Francesca Boscia
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Valentina Tedeschi
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Valeria de Rosa
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Pasquale Cepparulo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| | | | - Anna Pannaccione
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy
| |
Collapse
|