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Song N, Yu JE, Ji E, Choi KH, Lee S. Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells. Mol Cell Biochem 2024; 479:2653-2662. [PMID: 37861880 DOI: 10.1007/s11010-023-04881-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/07/2023] [Indexed: 10/21/2023]
Abstract
Aortic valve stenosis (AS) is the most common valvular heart disease but there are currently no effective medical treatments that can delay disease progression due to a lack of knowledge of the precise pathophysiology. The expression of sulfide: quinone oxidoreductase (SQOR) and nuclear factor erythroid 2-related factor 2 (NRF2) was decreased in the aortic valve of AS patients. However, the role of SQOR and NRF2 in the pathophysiology of AS has not been found. We investigated the effects of hydrogen sulfide (H2S)-releasing compounds on diseased aortic valve interstitial cells (AVICs) to explain the cellular mechanism of SQOR and elucidate the medical value of H2S for AS treatment. Sodium hydrosulfide (NaHS) treatment increased the expression of SQOR and NRF2 gene and consequently induced the NRF2 target genes, such as NAD(P)H quinone dehydrogenase 1 and cystathionine γ-lyase. In addition, NaHS dose-dependently decreased the expression level of fibrosis and inflammation-related genes (MMP9, TNF-α, IL6) and calcification-related genes (ALP, osteocalcin, RUNX2, COL1A1) in human AVICs. Furthermore, NaHS activated the AMPK-mTOR pathway and inhibited the PI3K-AKT pathway, resulting in a pro-autophagy effect in human AVICs. An NRF2 inhibitor, brusatol, attenuated NaHS-induced AMPK activation and decreased the autophagy markers Beclin-1 and LC3AB, suggesting that the mechanism of action of H2S is related to NRF2. In conclusion, H2S decreased gene expression levels related to aortic valve degeneration and activated AMPK-mTOR-mediated pro-autophagy function associated with NRF2 in human AVICs. Therefore, H2S could be a potential therapeutic target for the development of AS treatment.
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Affiliation(s)
- Naaleum Song
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, 88 Olympic-ro 43 Gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Jeong Eun Yu
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, 88 Olympic-ro 43 Gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Eunhye Ji
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyoung-Hee Choi
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sahmin Lee
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
- Department of Medical Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, 88 Olympic-ro 43 Gil, Songpa-gu, Seoul, 05505, Republic of Korea.
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Lian J, Chen Y, Zhang Y, Guo S, Wang H. The role of hydrogen sulfide regulation of ferroptosis in different diseases. Apoptosis 2024:10.1007/s10495-024-01992-z. [PMID: 38980600 DOI: 10.1007/s10495-024-01992-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2024] [Indexed: 07/10/2024]
Abstract
Ferroptosis is a programmed cell death that relies on iron and lipid peroxidation. It differs from other forms of programmed cell death such as necrosis, apoptosis and autophagy. More and more evidence indicates that ferroptosis participates in many types of diseases, such as neurodegenerative diseases, ischemia-reperfusion injury, cardiovascular diseases and so on. Hence, clarifying the role and mechanism of ferroptosis in diseases is of great significance for further understanding the pathogenesis and treatment of some diseases. Hydrogen sulfide (H2S) is a colorless and flammable gas with the smell of rotten eggs. Many years ago, H2S was considered as a toxic gas. however, in recent years, increasing evidence indicates that it is the third important gas signaling molecule after nitric oxide and carbon monoxide. H2S has various physiological and pathological functions such as antioxidant stress, anti-inflammatory, anti-apoptotic and anti-tumor, and can participate in various diseases. It has been reported that H2S regulation of ferroptosis plays an important role in many types of diseases, however, the related mechanisms are not fully clear. In this review, we reviewed the recent literature about the role of H2S regulation of ferroptosis in diseases, and analyzed the relevant mechanisms, hoping to provide references for future in-depth researches.
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Affiliation(s)
- Jingwen Lian
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yuhang Chen
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yanting Zhang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Shiyun Guo
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Honggang Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
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Le DE, Alkayed NJ, Cao Z, Chattergoon NN, Garcia-Jaramillo M, Thornburg K, Kaul S. Metabolomics of repetitive myocardial stunning in chronic multivessel coronary artery stenosis: Effect of non-selective and selective β1-receptor blockers. J Physiol 2024; 602:3423-3448. [PMID: 38885335 PMCID: PMC11284965 DOI: 10.1113/jp285720] [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: 09/24/2023] [Accepted: 05/29/2024] [Indexed: 06/20/2024] Open
Abstract
Chronic coronary artery stenosis can lead to regional myocardial dysfunction in the absence of myocardial infarction by repetitive stunning, hibernation or both. The molecular mechanisms underlying repetitive stunning-associated myocardial dysfunction are not clear. We used non-targeted metabolomics to elucidate responses to chronically stunned myocardium in a canine model with and without β-adrenergic blockade treatment. After development of left ventricular systolic dysfunction induced by ameroid constrictors on the coronary arteries, animals were randomized to 3 months of placebo, metoprolol or carvedilol. We compared these two β-blockers with their different β-adrenergic selectivities on myocardial function, perfusion and metabolic pathways involved in tissue undergoing chronic stunning. Control animals underwent sham surgery. Dysfunction in stunned myocardium was associated with reduced fatty acid oxidation and enhanced ketogenic amino acid metabolism, together with alterations in mitochondrial membrane phospholipid composition. These changes were consistent with impaired mitochondrial function and were linked to reduced nitric oxide and peroxisome proliferator-activated receptor signalling, resulting in a decline in adenosine monophosphate-activated protein kinase. Mitochondrial changes were ameliorated by carvedilol more than metoprolol, and improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. In summary, repetitive myocardial stunning commonly seen in chronic multivessel coronary artery disease is associated with adverse metabolic remodelling linked to mitochondrial dysfunction and specific signalling pathways. These changes are reversed by β-blockers, with the non-selective inhibitor having a more favourable impact. This is the first investigation to demonstrate that β-blockade-associated improvement of ventricular function in chronic myocardial stunning is associated with restoration of mitochondrial function. KEY POINTS: The mechanisms responsible for the metabolic changes associated with repetitive myocardial stunning seen in chronic multivessel coronary artery disease have not been fully investigated. In a canine model of repetitive myocardial stunning, we showed that carvedilol, a non-selective β-receptor blocker, ameliorated adverse metabolic remodelling compared to metoprolol, a selective β1-receptor blocker, by improving nitric oxide synthase and adenosine monophosphate protein kinase function, enhancing calcium/calmodulin-dependent protein kinase, probably increasing hydrogen sulphide, and suppressing cyclic-adenosine monophosphate signalling. Mitochondrial fatty acid oxidation alterations were ameliorated by carvedilol to a larger extent than metoprolol; this improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. Both β-blockers improved the cardiac energy imbalance by reducing metabolites in ketogenic amino acid and nucleotide metabolism. These results elucidated why metabolic remodelling with carvedilol is preferable to metoprolol when treating chronic ischaemic left ventricular systolic dysfunction caused by repetitive myocardial stunning.
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Affiliation(s)
- D. Elizabeth Le
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
- Veterans Affairs Portland Health Care System, Portland, OR, USA
| | - Nabil J. Alkayed
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Zhiping Cao
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Natasha N. Chattergoon
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
| | - Manuel Garcia-Jaramillo
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA
| | - Kent Thornburg
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
| | - Sanjiv Kaul
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
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Li J, Xie Y, Zheng S, He H, Wang Z, Li X, Jiao S, Liu D, Yang F, Zhao H, Li P, Sun Y. Targeting autophagy in diabetic cardiomyopathy: From molecular mechanisms to pharmacotherapy. Biomed Pharmacother 2024; 175:116790. [PMID: 38776677 DOI: 10.1016/j.biopha.2024.116790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.
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Affiliation(s)
- Jie Li
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, China
| | - Yingying Xie
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuwen Zheng
- Beijing University of Chinese Medicine School of Traditional Chinese Medicine, Beijing, China
| | - Haoming He
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhe Wang
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xuexi Li
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Siqi Jiao
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Dong Liu
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Furong Yang
- Beijing University of Chinese Medicine School of Traditional Chinese Medicine, Beijing, China
| | - Hailing Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
| | - Yihong Sun
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.
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Flori L, Benedetti G, Calderone V, Testai L. Hydrogen Sulfide and Irisin, Potential Allies in Ensuring Cardiovascular Health. Antioxidants (Basel) 2024; 13:543. [PMID: 38790648 PMCID: PMC11118251 DOI: 10.3390/antiox13050543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/19/2024] [Accepted: 04/27/2024] [Indexed: 05/26/2024] Open
Abstract
Irisin is a myokine secreted under the influence of physical activity and exposure to low temperatures and through different exogenous stimuli by the cleavage of its precursor, fibronectin type III domain-containing protein 5 (FNDC5). It is mainly known for maintaining of metabolic homeostasis, promoting the browning of white adipose tissue, the thermogenesis process, and glucose homeostasis. Growing experimental evidence suggests the possible central role of irisin in the regulation of cardiometabolic pathophysiological processes. On the other side, hydrogen sulfide (H2S) is well recognized as a pleiotropic gasotransmitter that regulates several homeostatic balances and physiological functions and takes part in the pathogenesis of cardiometabolic diseases. Through the S-persulfidation of cysteine protein residues, H2S is capable of interacting with crucial signaling pathways, exerting beneficial effects in regulating glucose and lipid homeostasis as well. H2S and irisin seem to be intertwined; indeed, recently, H2S was found to regulate irisin secretion by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/FNDC5/irisin signaling pathway, and they share several mechanisms of action. Their involvement in metabolic diseases is confirmed by the detection of their lower circulating levels in obese and diabetic subjects. Along with the importance of metabolic disorders, these modulators exert favorable effects against cardiovascular diseases, preventing incidents of hypertension, atherosclerosis, heart failure, myocardial infarction, and ischemia-reperfusion injury. This review, for the first time, aims to explore the role of H2S and irisin and their possible crosstalk in cardiovascular diseases, pointing out the main effects exerted through the common molecular pathways involved.
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Affiliation(s)
- Lorenzo Flori
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (L.F.); (G.B.); (V.C.)
| | - Giada Benedetti
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (L.F.); (G.B.); (V.C.)
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (L.F.); (G.B.); (V.C.)
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56120 Pisa, Italy
- Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, 56120 Pisa, Italy
| | - Lara Testai
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (L.F.); (G.B.); (V.C.)
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56120 Pisa, Italy
- Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, 56120 Pisa, Italy
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Golpasandi H, Rahimi MR, Ahmadi S, Łubkowska B, Cięszczyk P. Effects of Vitamin D3 Supplementation and Aerobic Training on Autophagy Signaling Proteins in a Rat Model Type 2 Diabetes Induced by High-Fat Diet and Streptozotocin. Nutrients 2023; 15:4024. [PMID: 37764807 PMCID: PMC10535215 DOI: 10.3390/nu15184024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/15/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
The aim of this study was to investigate the combined effects of vitamin D3 supplementation and aerobic training on regulating the autophagy process in rats with type 2 diabetic induced by a high-fat diet and streptozotocin. A total of 40 Wistar rats were divided into five groups: normal control (NC), diabetic control (DC), diabetic + aerobic training (DAT), diabetic + vitamin D3 (DVD), and diabetic + aerobic training + vitamin D3 (DVDAT). The rats underwent eight weeks of aerobic training with an intensity of 60% maximum running speed for one hour, along with weekly subcutaneous injections of 10,000 units of vitamin D3. The protein levels of different autophagy markers were assessed in the left ventricular heart tissue. The results showed that the protein levels of AMPK, pAMPK, mTOR, and pmTOR were significantly lower in the DC group compared to the NC group. Conversely, the levels of ULK, Beclin-1, LC3II, Fyco, and Cathepsin D proteins were significantly higher in the DC group. However, the interventions of aerobic training and vitamin D3 supplementation, either individually or in combination, led to increased levels of AMPK, pAMPK, mTOR, and pmTOR, and decreased levels of ULK, Beclin-1, LC3II, Fyco, and Cathepsin D (p < 0.05). Additionally, the aerobic capacity in the DAT and DVDAT groups was significantly higher compared to the NC, DC, and DVD groups (p < 0.05). These findings suggest that type 2 diabetes is associated with excessive autophagy in the left ventricle. However, after eight weeks of vitamin D3 supplementation and aerobic training, a significant reduction in excessive autophagy was observed in rats with type 2 diabetes.
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Affiliation(s)
- Hadi Golpasandi
- Department of Exercise Physiology, University of Kurdistan, Sanandaj 66177-15175, Iran;
| | | | - Slahadin Ahmadi
- Department of Physiology and Pharmacology, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj 66186-34683, Iran;
| | - Beata Łubkowska
- Faculty of Health and Life Sciences, Gdansk University of Physical Education and Sport, Gorskiego 1, 80-336 Gdansk, Poland; (B.Ł.); (P.C.)
| | - Paweł Cięszczyk
- Faculty of Health and Life Sciences, Gdansk University of Physical Education and Sport, Gorskiego 1, 80-336 Gdansk, Poland; (B.Ł.); (P.C.)
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Seksaria S, Mehan S, Dutta BJ, Gupta GD, Ganti SS, Singh A. Oxymatrine and insulin resistance: Focusing on mechanistic intricacies involve in diabetes associated cardiomyopathy via SIRT1/AMPK and TGF-β signaling pathway. J Biochem Mol Toxicol 2023; 37:e23330. [PMID: 36890713 DOI: 10.1002/jbt.23330] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/03/2023] [Accepted: 02/09/2023] [Indexed: 03/10/2023]
Abstract
Cardiomyopathy (CDM) and related morbidity and mortality are increasing at an alarming rate, in large part because of the increase in the number of diabetes mellitus cases. The clinical consequence associated with CDM is heart failure (HF) and is considerably worse for patients with diabetes mellitus, as compared to nondiabetics. Diabetic cardiomyopathy (DCM) is characterized by structural and functional malfunctioning of the heart, which includes diastolic dysfunction followed by systolic dysfunction, myocyte hypertrophy, cardiac dysfunctional remodeling, and myocardial fibrosis. Indeed, many reports in the literature indicate that various signaling pathways, such as the AMP-activated protein kinase (AMPK), silent information regulator 1 (SIRT1), PI3K/Akt, and TGF-β/smad pathways, are involved in diabetes-related cardiomyopathy, which increases the risk of functional and structural abnormalities of the heart. Therefore, targeting these pathways augments the prevention as well as treatment of patients with DCM. Alternative pharmacotherapy, such as that using natural compounds, has been shown to have promising therapeutic effects. Thus, this article reviews the potential role of the quinazoline alkaloid, oxymatrine obtained from the Sophora flavescensin CDM associated with diabetes mellitus. Numerous studies have given a therapeutic glimpse of the role of oxymatrine in the multiple secondary complications related to diabetes, such as retinopathy, nephropathy, stroke, and cardiovascular complications via reductions in oxidative stress, inflammation, and metabolic dysregulation, which might be due to targeting signaling pathways, such as AMPK, SIRT1, PI3K/Akt, and TGF-β pathways. Thus, these pathways are considered central regulators of diabetes and its secondary complications, and targeting these pathways with oxymatrine might provide a therapeutic tool for the diagnosis and treatment of diabetes-associated cardiomyopathy.
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Affiliation(s)
- Sanket Seksaria
- Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India
| | - Sidharth Mehan
- Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India
| | - Bhaskar J Dutta
- Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India
| | - Ghanshyam D Gupta
- Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India
| | - Subrahmanya S Ganti
- Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India
| | - Amrita Singh
- Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India
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Mathur P, Rani V. Investigating microRNAs in diabetic cardiomyopathy as tools for early detection and therapeutics. Mol Cell Biochem 2023; 478:229-240. [PMID: 35779226 DOI: 10.1007/s11010-022-04473-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 05/04/2022] [Indexed: 02/02/2023]
Abstract
To profile microRNAs population of glucose-induced cardiomyoblast cell line and identify the differentially expressed microRNAs and their role under pre-diabetes and diabetes condition in vitro. Rat fetal ventricular cardiomyoblast cell line H9c2 was treated with D-glucose to mimic pre-diabetic, diabetic, and high-glucose conditions. Alteration in cellular, nuclear morphology, and change in ROS generation was analyzed through fluorescent staining. Small RNA sequencing was performed using Illumina NextSeq 550 sequencer and was validated using stem-loop qRT-PCR. A large number (~ 100) differential miRNAs were detected in each treated samples as compared to control; however, a similar expression pattern was observed between pre-diabetes and diabetes conditions with the exception for miR-429, miR-101b-5p, miR-503-3p, miR-384-5p, miR-412-5p, miR-672-5p, and miR-532-3p. Functional annotation of differential expressed target genes revealed their involvement in significantly enriched key pathways associated with diabetic cardiomyopathy. For the first time, we report the differential expression of miRNAs (miR-1249, miR-3596d, miR- 3586-3p, miR-7b-3p, miR-191, miR-330-3p, miR-328a, let7i-5p, miR-146-3p, miR-26a-3p) in diabetes-induced cardiac cells. Hyperglycemia threatens the cell homeostasis by dysregulation of miRNAs that begins at a glucose level 10 mM and remains undetected. Analysis of differential expressed miRNAs in pre-diabetes and diabetes conditions and their role in regulatory mechanisms of diabetic cardiomyopathy holds high potential in the direction of using miRNAs as minimally invasive diagnostic and therapeutic tools.
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Affiliation(s)
- Priyanka Mathur
- Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh, 210309, India
| | - Vibha Rani
- Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh, 210309, India.
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Zhao H, Fu X, Zhang Y, Yang Y, Wang H. Hydrogen sulfide plays an important role by regulating endoplasmic reticulum stress in myocardial diseases. Front Pharmacol 2023; 14:1172147. [PMID: 37124222 PMCID: PMC10133551 DOI: 10.3389/fphar.2023.1172147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/04/2023] [Indexed: 05/02/2023] Open
Abstract
Endoplasmic reticulum (ER) is an important organelle for protein translation, folding and translocation, as well as the post-translational modification and assembly of newly synthesized secreted proteins. When the excessive accumulation of misfolded and/or unfolded proteins exceeds the processing capacity of ER, ER stress is triggered. The integrated intracellular signal cascade, namely the unfolded protein response, is induced to avoid ER stress. ER stress is involved in many pathological and physiological processes including myocardial diseases. For a long time, hydrogen sulfide (H2S) has been considered as a toxic gas with the smell of rotten eggs. However, more and more evidences indicate that H2S is an important gas signal molecule after nitric oxide and carbon monoxide, and regulates a variety of physiological and pathological processes in mammals. In recent years, increasing studies have focused on the regulatory effects of H2S on ER stress in myocardial diseases, however, the mechanism is not very clear. Therefore, this review focuses on the role of H2S regulation of ER stress in myocardial diseases, and deeply analyzes the relevant mechanisms so as to lay the foundation for the future researches.
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Affiliation(s)
- Huijie Zhao
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Xiaodi Fu
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
| | - Yanting Zhang
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Yihan Yang
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Honggang Wang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
- *Correspondence: Honggang Wang,
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Yu Q, Tu L, Zhu T, Zhu H, Liu S, Sun Y, Zhao Q. Hypoxia-Activatable Nanovesicles as In Situ Bombers for Combined Hydrogen-Sulfide-Mediated Respiration Inhibition and Photothermal Therapy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:50637-50648. [PMID: 36326806 DOI: 10.1021/acsami.2c15844] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Photothermal therapy (PTT) has emerged as a promising alternative or supplement to cancer treatments. While PTT induces the ablation of solid tumors, its efficiency is hampered by self-recovery within impaired cancer cells through glycolysis and respiration metabolism. Based on this, the introduction of hydrogen sulfide (H2S)-mediated respiration inhibition is a good choice to make up for the PTT limitation. Herein, nanovesicles (NP1) are integrated by a hypoxia-responsive conjugated polymer (P1), polymetric H2S donor (P2), and near-infrared (NIR) light-harvesting aza-BODIPY dye (B1) for the delivery of H2S and synergistic H2S gas therapy/PTT. The scaffold of NP1 undergoes disassembly in the hypoxic environments, thus triggering the hydrolysis of P2 to continuously long-term release H2S. Dependent on the superior photothermal ability of B1, NP1 elicits high photothermal conversion efficiency (η = 19.9%) under NIR light irradiation for PTT. Moreover, NP1 serves as in situ H2S bombers in the hypoxic tumor environment and suppresses the mitochondrial respiration through inhibiting expression of cytochrome c oxidase (COX IV) and cutting off the adenosine triphosphate (ATP) generation. Both in vitro and in vivo results demonstrate good antitumor efficacy of H2S gas therapy/PTT, which will be recommended as an advanced strategy for cancer therapeutics.
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Affiliation(s)
- Qi Yu
- Key Laboratory of Fermentation Engineering (Ministry of Education), National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Key Laboratory of Industrial Microbiology, School of Food and Biological Engineering, Hubei University of Technology, Wuhan 430068, P.R. China
| | - Le Tu
- Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P.R. China
| | - Ting Zhu
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) & Institute of Flexible Electronics (Future Technology), Nanjing University of Posts and Telecommunications (NUPT), Nanjing 210023, P.R. China
| | - Hongda Zhu
- Key Laboratory of Fermentation Engineering (Ministry of Education), National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Key Laboratory of Industrial Microbiology, School of Food and Biological Engineering, Hubei University of Technology, Wuhan 430068, P.R. China
| | - Shujuan Liu
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) & Institute of Flexible Electronics (Future Technology), Nanjing University of Posts and Telecommunications (NUPT), Nanjing 210023, P.R. China
| | - Yao Sun
- Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P.R. China
| | - Qiang Zhao
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) & Institute of Flexible Electronics (Future Technology), Nanjing University of Posts and Telecommunications (NUPT), Nanjing 210023, P.R. China
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11
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Hydrogen Sulfide and Its Donors: Keys to Unlock the Chains of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms232012202. [PMID: 36293058 PMCID: PMC9603526 DOI: 10.3390/ijms232012202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/30/2022] [Accepted: 10/09/2022] [Indexed: 11/17/2022] Open
Abstract
Hydrogen sulfide (H2S) has emerged as the third “gasotransmitters” and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced.
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12
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Li H, Wei Y, Xi Y, Jiao L, Wen X, Wu R, Chang G, Sun F, Hao J. DR1-CSE/H 2S pathway upregulates autophagy and inhibits H9C2 cells damage induced by high glucose. Acta Cardiol 2022:1-13. [PMID: 36197015 DOI: 10.1080/00015385.2022.2119663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
In the cardiovascular system, long-term high glucose (HG) can lead to cardiomyocyte damage. Hydrogen sulfide (H2S) reduces cell autophagy in cardiomyocytes. Dopamine 1 receptors (DR1), a specific binding receptor for dopamine, which has a significant regulatory effect on cardiomyocytes. However, it is unclear whether DR1 inhibits HG-induced cardiomyocyte damage by regulating endogenous H2S production and the level of cell autophagy. The present data indicated that the expression of DR1 and cystathionine-γ-lyase (CSE, a key enzyme for endogenous H2S production) and H2S content were significantly reduced in HG-induced cardiomyocytes, which was reversed by SKF38393 (an agonist of DR1). NaHS (an exogenous H2S donor) only increased H2S content and the expression of CSE with no effect on DR1 expression. HG reduced cell viability, the expression of Bcl-2 and Beclin1, the production of autophagosomes and LC3 II/I ratio and increased the cell apoptotic ratio, the expression of cleaved caspase-3, cleaved caspase-9, cytochrome c, P62, and p-mTOR/t-mTOR ratio. SKF38393 and NaHS reversed the effects of HG. PPG (an inhibitor of CSE) and 3MA (an inhibitor of autophagy) abolished the beneficial effect of SKF38393. In addition, AICAR (an agonist of AMPK) and Rapamycin (an inhibitor of mTOR) increased the production of autophagosomes but decreased the p-mTOR/t-mTOR ratio, which was similar to the effects of SKF38393 and 3MA. Our findings suggest that DR1 reduces the HG-induced cardiomyocyte damage via up-regulating the CSE/H2S pathway, which increases cell autophagy by inhibiting the activation of mTOR.
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Affiliation(s)
- Hongzhu Li
- School of Medicine, Xiamen University, Xiamen, China.,Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Yaxin Wei
- Department of Pathophysiology, Harbin Medical University, Harbin, China.,Department of Pathology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Yuxin Xi
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Lijie Jiao
- School of Medicine, Xiamen University, Xiamen, China
| | - Xin Wen
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Ren Wu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Guiquan Chang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Fengqi Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Jinghui Hao
- Department of Pathophysiology, Harbin Medical University, Harbin, China
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13
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Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter. Antioxidants (Basel) 2022; 11:antiox11091788. [PMID: 36139861 PMCID: PMC9495975 DOI: 10.3390/antiox11091788] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/04/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
Hydrogen sulfide has been recently identified as the third biological gasotransmitter, along with the more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential as a therapeutic agent for cardiovascular, inflammatory, infectious and neuropathological diseases have been undertaken. Here we review the possible direct targets of H2S in mammals. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling. H2S also reacts with hemeproteins and modulates metal-containing complexes. Once being oxidized, H2S can persulfidate proteins by adding -SSH to the amino acid cysteine. These direct modifications by H2S have significant impact on cell structure and many cellular functions, such as tight junctions, autophagy, apoptosis, vesicle trafficking, cell signaling, epigenetics and inflammasomes. Therefore, we conclude that H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases.
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14
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Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice. Signal Transduct Target Ther 2022; 7:259. [PMID: 35909160 PMCID: PMC9339545 DOI: 10.1038/s41392-022-01054-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 05/06/2022] [Accepted: 06/05/2022] [Indexed: 02/08/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17α-MHCKO and ADAM17fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM. Proposed mechanisms underlying the salutary effects of ADAM17 deficiency on diabetic cardiomyopathy. ADAM17 deficiency increases autophagosome formation and improves autophagic flux via reducing ACE2 shedding, activating AMPK pathway, and promoting TFEB nuclear translocation, which reduces the apoptotic response in cardiomyocytes and attenuates left ventricular remodeling and dysfunction in DCM of mice. ![]()
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15
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Dugbartey GJ, Wonje QL, Alornyo KK, Adams I, Diaba DE. Alpha-lipoic acid treatment improves adverse cardiac remodelling in the diabetic heart - The role of cardiac hydrogen sulfide-synthesizing enzymes. Biochem Pharmacol 2022; 203:115179. [PMID: 35853498 DOI: 10.1016/j.bcp.2022.115179] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/26/2022] [Accepted: 07/12/2022] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Alpha-lipoic acid (ALA) is a licensed drug for the treatment of diabetic neuropathy. We recently reported that it also improves diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus (T2DM). In this study, we present evidence supporting our hypothesis that the cardioprotective effect of ALA is via upregulation of cardiac hydrogen sulfide (H2S)-synthesizing enzymes. METHODS Following 12 h of overnight fasting, T2DM was induced in 23 out of 30 male Sprague-Dawley rats by intraperitoneal administration of nicotinamide (110 mg/kg) followed by streptozotocin (55 mg/kg) while the rest served as healthy control (HC). T2DM rats then received either oral administration of ALA (60 mg/kg/day; n = 7) or 40 mg/kg/day DL-propargylglycine (PAG, an endogenous H2S inhibitor; n = 7) intraperitoneally for 6 weeks after which all rats were sacrificed and samples collected for analysis. Untreated T2DM rats served as diabetic control (DCM; n = 9). RESULTS T2DM resulted in weight loss, islet destruction, reduced pancreatic β-cell function and hyperglycemia. Histologically, DCM rats showed significant myocardial damage evidenced by myocardial degeneration, cardiomyocyte vacuolation and apoptosis, cardiac fibrosis and inflammation, which positively correlated with elevated levels of cardiac damage markers compared to HC rats (p < 0.001). These pathological alterations worsened significantly in PAG-treated rats (p < 0.05). However, ALA treatment restored normoinsulemia, normoglycemia, prevented DCM, and improved lipid and antioxidant status. Mechanistically, ALA significantly upregulated the expression of cardiac H2S-synthesizing enzymes and increased plasma H2S concentration compared to DCM rats (p < 0.001). CONCLUSION ALA preserves myocardial integrity in T2DM likely by maintaining the expression of cardiac H2S-synthezing enzymes and increasing plasma H2S level.
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Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana.
| | - Quinsker L Wonje
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Karl K Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Ismaila Adams
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Deborah E Diaba
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
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16
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Hydrogen Sulfide Regulates Irisin and Glucose Metabolism in Myotubes and Muscle of HFD-Fed Diabetic Mice. Antioxidants (Basel) 2022; 11:antiox11071369. [PMID: 35883859 PMCID: PMC9311985 DOI: 10.3390/antiox11071369] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/04/2022] [Accepted: 07/13/2022] [Indexed: 12/26/2022] Open
Abstract
Irisin, a novel myokine, is secreted by the muscle following proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5) and is considered a novel regulator of glucose homeostasis. Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) and is involved in glucose homeostasis. We examined the hypothesis that H2S deficiency leads to decreased FNDC5 and irisin secretion, and thereby alters glucose metabolism. High-fat diet-fed mice exhibited elevated blood glucose and significantly reduced levels of CSE, H2S, and PGC-1α, with decreased FNDC5/irisin levels and increased oxidative stress in the muscle compared with those of normal diet-fed mice (control). High glucose or palmitate decreases CSE/PGC-1α/FNDC5 levels and glucose uptake in myotubes. Inhibitors (propargylglycine and aminooxyacetate) of H2S producing enzymes or CSE siRNA significantly decreased levels of H2S and FNDC5 along with PGC-1α; similar H2S-deficient conditions also resulted in decreased GLUT4 and glucose uptake. The levels of H2S, PGC-1α, and FNDC5 and glucose uptake were significantly upregulated after treatment with l-cysteine or an H2S donor. Myoblast differentiation showed upregulation of PGC-1α and FNDC5, which was consistent with the increased expression of CSE/H2S. These findings suggest that the upregulation of H2S levels can have beneficial effects on glucose homeostasis via activation of the PGC-1α/FNDC5/irisin signaling pathway.
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17
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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18
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Li T, Zhao J, Miao S, Chen Y, Xu Y, Liu Y. Protective effect of H 2S on LPS‑induced AKI by promoting autophagy. Mol Med Rep 2022; 25:96. [PMID: 35059738 PMCID: PMC8809055 DOI: 10.3892/mmr.2022.12612] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/17/2021] [Indexed: 11/06/2022] Open
Abstract
The present study explored the protective effect of exogenous hydrogen sulfide (H2S) on lipopolysaccharide (LPS)‑induced acute kidney injury (AKI) and the underlying mechanisms. To establish an AKI injury mouse model, LPS (10 mg/kg) was intraperitoneally injected into mice pretreated with 0.8 mg/kg sodium hydrosulfide hydrate (NaHS), an H2S donor. The mouse survival rate and the degree of kidney injury were examined. To construct a cell damage model, HK‑2 cells were pretreated with different concentrations (0.1, 0.3 and 0.5 mM) of NaHS, and then the cells were stimulated with LPS (1 µg/ml). The cell viability, autophagy, apoptosis levels and the release of inflammatory factors were examined in mouse kidney tissue and HK‑2 renal tubular epithelial cells. It was found that pretreatment with NaHS significantly improved the survival rate of septic AKI mice, and reduced the renal damage, release of inflammatory factors and apoptosis. In HK‑2 cells, NaHS protected cells from LPS caused damage via promoting autophagy and inhibiting apoptosis and the release of inflammatory factors. In order to clarify the relationship between autophagy and apoptosis and inflammatory factors, this study used 3‑methyladenine (3‑MA) to inhibit autophagy. The results revealed that 3‑MA eliminated the protective effect of NaHS in HK‑2 cells and AKI mice. Overall, NaHS can protect from LPS‑induced AKI by promoting autophagy and inhibiting apoptosis and the release of inflammatory factors.
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Affiliation(s)
- Ting Li
- Department of Physiology, Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Jie Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China
| | - Shuying Miao
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China
| | - Yiyang Chen
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China
| | - Yunfei Xu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China
| | - Ying Liu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China
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19
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Uncoupling protein 1 knockout aggravates isoproterenol-induced acute myocardial ischemia via AMPK/mTOR/PPARα pathways in rats. Transgenic Res 2021; 31:107-118. [PMID: 34709566 PMCID: PMC8821478 DOI: 10.1007/s11248-021-00289-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/01/2021] [Indexed: 11/17/2022]
Abstract
Uncoupling protein 1 (UCP1) was found exclusively in the inner membranes of the mitochondria of brown adipose tissue (BAT). We found that UCP1 was also expressed in heart tissue and significantly upregulated in isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rat model. The present study is to determine the underlying mechanism involved in the UCP1 upregulation in ISO-induced AMI rat model. The Ucp1−/− rats were generated by CRISPR-Cas9 system and presented decreased BAT volume. 2-months old Sprague Dawley (SD) wild-type (WT) and Ucp1−/− rats were treated with ISO intraperitoneally 30 mg/kg once a day for 3 consecutive days to establish AMI model. In saline group, the echocardiographic parameters, serum markers of myocardial injury cardiac troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), oxidant malondialdehyde (MDA), antioxidant superoxide dismutase (SOD) or fibrosis were comparable between WT and Ucp1−/− rats. ISO treatment induced worse left ventricle (LV) hypertrophy, myocardial fibrosis, increased higher cTnI, CK-MB and MDA and decreased lower SOD level in Ucp1−/− rats compared with that of WT rats. Ucp1−/− rats also presented lower myocardial phosphocreatine (PCr)/ATP-ratio, which demonstrated worse cardiac energy regulation defect. ISO treatment induced the phosphorylation of AMP-activated protein kinase (AMPK) activation, subsequently the phosphorylation of mammalian target of rapamycin (mTOR) inhibition and peroxisome proliferators-activated receptor α (PPARα) activation in WT rats, whereas activation of AMPK/mTOR/PPARα pathways significantly inhibited in Ucp1−/− rats. To sum up, UCP1 knockout aggravated ISO-induced AMI by inhibiting AMPK/mTOR/PPARα pathways in rats. Increasing UCP1 expression in heart tissue may be a cytoprotective therapeutic strategy for AMI.
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20
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Hydrogen sulfide plays a potential alternative for the treatment of metabolic disorders of diabetic cardiomyopathy. Mol Cell Biochem 2021; 477:255-265. [PMID: 34687394 DOI: 10.1007/s11010-021-04278-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/13/2021] [Indexed: 12/16/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a cardiovascular complication that tends to occur in patients with diabetes, obesity, or insulin resistance, with a higher late mortality rate. Sustained hyperglycemia, increased free fatty acids, or insulin resistance induces metabolic disorders in cardiac tissues and cells, leading to myocardial fibrosis, left ventricular hypertrophy, diastolic and/or systolic dysfunction, and finally develop into congestive heart failure. The close connection between all signaling pathways and the complex pathogenesis of DCM cause difficulties in finding effective targets for the treatment of DCM. It reported that hydrogen sulfide (H2S) could regulate cell energy substrate metabolism, reduce insulin resistance, protect cardiomyocytes, and improve myocardial function by acting on related key proteins such as differentiation cluster 36 (CD36) and glucose transporter 4 (GLUT4). In this article, the relative mechanisms of H2S in alleviating metabolic disorders of DCM were reviewed, and how H2S can better prevent and treat DCM in clinical practice will be discussed.
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21
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Hydrogen sulfide in ageing, longevity and disease. Biochem J 2021; 478:3485-3504. [PMID: 34613340 PMCID: PMC8589328 DOI: 10.1042/bcj20210517] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 12/21/2022]
Abstract
Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.
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22
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Dewanjee S, Vallamkondu J, Kalra RS, John A, Reddy PH, Kandimalla R. Autophagy in the diabetic heart: A potential pharmacotherapeutic target in diabetic cardiomyopathy. Ageing Res Rev 2021; 68:101338. [PMID: 33838320 DOI: 10.1016/j.arr.2021.101338] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/24/2021] [Accepted: 03/29/2021] [Indexed: 12/20/2022]
Abstract
Association of diabetes with an elevated risk of cardiac failure has been clinically evident. Diabetes potentiates diastolic and systolic cardiac failure following the myocardial infarction that produces the cardiac muscle-specific microvascular complication, clinically termed as diabetic cardiomyopathy. Elevated susceptibility of diabetic cardiomyopathy is primarily caused by the generation of free radicals in the hyperglycemic milieu, compromising the myocardial contractility and normal cardiac functions with increasing redox insult, impaired mitochondria, damaged organelles, apoptosis, and cardiomyocytes fibrosis. Autophagy is essentially involved in the recycling/clearing the damaged organelles, cytoplasmic contents, and aggregates, which are frequently produced in cardiomyocytes. Although autophagy plays a vital role in maintaining the cellular homeostasis in diligent cardiac tissues, this process is frequently impaired in the diabetic heart. Given its clinical significance, accumulating evidence largely showed the functional aspects of autophagy in diabetic cardiomyopathy, elucidating its intricate protective and pathogenic outcomes. However, etiology and molecular readouts of these contrary autophagy activities in diabetic cardiomyopathy are not yet comprehensively assessed and translated. In this review, we attempted to assess the role of autophagy and its adaptations in the diabetic heart. To delineate the molecular consequences of these events, we provided detailed insights into the autophagy regulation pieces of machinery including the mTOR/AMPK, TFEB/ZNSCAN3, FOXOs, SIRTs, PINK1/Parkin, Nrf2, miRNAs, and others in the diabetic cardiomyopathy. Given the clinical significance of autophagy in the diabetic heart, we further discussed the potential pharmacotherapeutic strategies towards targeting autophagy. Taken together, the present report meticulously assessed autophagy, its adaptations, and molecular regulations in diabetic cardiomyopathy and reviewed the current autophagy-targeting strategies.
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Affiliation(s)
- Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | | | - Rajkumar Singh Kalra
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Higashi 1-1-1, Tsukuba, 305 8565, Japan.
| | - Albin John
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
| | - Ramesh Kandimalla
- Department of Biochemistry, Kakatiya Medical College, Warangal, 506007, Telangana, India; Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad, 50000, Telangana, India.
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23
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Lv S, Liu H, Wang H. Exogenous Hydrogen Sulfide Plays an Important Role by Regulating Autophagy in Diabetic-Related Diseases. Int J Mol Sci 2021; 22:ijms22136715. [PMID: 34201520 PMCID: PMC8268438 DOI: 10.3390/ijms22136715] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/21/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a vital cell mechanism which plays an important role in many physiological processes including clearing long-lived, accumulated and misfolded proteins, removing damaged organelles and regulating growth and aging. Autophagy also participates in a variety of biological functions, such as development, cell differentiation, resistance to pathogens and nutritional hunger. Recently, autophagy has been reported to be involved in diabetes, but the mechanism is not fully understood. Hydrogen sulfide (H2S) is a colorless, water-soluble, flammable gas with the typical odor of rotten eggs, which has been known as a highly toxic gas for many years. However, it has been reported recently that H2S, together with nitric oxide and carbon monoxide, is an important gas signal transduction molecule. H2S has been reported to play a protective role in many diabetes-related diseases, but the mechanism is not fully clear. Recent studies indicate that H2S plays an important role by regulating autophagy in many diseases including cancer, tissue fibrosis diseases and glycometabolic diseases; however, the related mechanism has not been fully studied. In this review, we summarize recent research on the role of H2S in regulating autophagy in diabetic-related diseases to provide references for future related research.
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24
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Wei L, Jian P, Erjiong H, Qihan Z. Ginkgetin alleviates high glucose-evoked mesangial cell oxidative stress injury, inflammation, and extracellular matrix (ECM) deposition in an AMPK/mTOR-mediated autophagy axis. Chem Biol Drug Des 2021; 98:620-630. [PMID: 34148304 DOI: 10.1111/cbdd.13915] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/14/2021] [Accepted: 06/12/2021] [Indexed: 11/28/2022]
Abstract
Diabetic nephropathy constitutes the leading cause for end-stage kidney disease. Ginkgetin is a common natural non-toxic biflavone and fulfills pleiotropic pharmacological characterizations, such as anti-inflammation and kidney injury. Nevertheless, its efficacy in diabetic nephropathy remains elusive. Here, ginkgetin exhibited little cytotoxicity in glomerular mesangial cells. Of note, ginkgetin restrained high glucose (HG)-induced mesangial cell proliferation and oxidative stress by inhibiting ROS and malonaldehyde levels, but enhancing antioxidant SOD activity. Additionally, ginkgetin suppressed HG-evoked transcript and release of inflammatory cytokine TNF-α, IL-1β, and IL-6. Concomitantly, the increased extracellular matrix (ECM) deposition in HG-treated glomerular mesangial cells was attenuated by ginkgetin via decreasing expression of collagen IV, fibronectin, and laminin. Intriguingly, ginkgetin-restored HG-impaired autophagy; whereas blocking autophagy by its inhibitor 3-MA overturned ginkgetin function against HG-evoked mesangial cell dysfunction. Mechanistically, ginkgetin-mediated AMPK/mTOR axis accounted for HG-impaired autophagy. Importantly, blockage of AMPK signaling reversed ginkgetin-restored autophagy and its protective efficacy against HG-induced dysfunction in mesangial cells. Thus, these findings highlight that ginkgetin may attenuate HG-evoked mesangial cell hyperplasia, oxidative stress, inflammation, and ECM accumulation by activating AMPk/mTOR-mediated autophagy pathway. Therefore, ginkgetin may alleviate the progression of diabetic nephropathy by regulating glomerular mesangial cell dysfunction, supporting a promising therapeutic agent against diabetic nephropathy.
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Affiliation(s)
- Lin Wei
- Departments of General Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pan Jian
- Departments of Ophthalmology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huang Erjiong
- Departments of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhu Qihan
- Departments of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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25
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Zhu Y, Su Y, Zhang J, Zhang Y, Li Y, Han Y, Dong X, Li W, Li W. Astragaloside IV alleviates liver injury in type 2 diabetes due to promotion of AMPK/mTOR‑mediated autophagy. Mol Med Rep 2021; 23:437. [PMID: 33846768 PMCID: PMC8060804 DOI: 10.3892/mmr.2021.12076] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open
Abstract
Diabetic liver injury is a serious complication of type 2 diabetes mellitus (T2DM), which is often irreversible in the later stage, and affects the quality of life. Autophagy serves an important role in the occurrence and development of diabetic liver injury. For example, it can improve insulin resistance (IR), dyslipidaemia, oxidative stress and inflammation. Astragaloside IV (AS-IV) is a natural saponin isolated from the plant Astragalus membranaceus, which has comprehensive pharmacological effects, such as anti-oxidation, anti-inflammation and anti-apoptosis properties, as well as can enhance immunity. However, whether AS-IV can alleviate diabetic liver injury in T2DM and its underlying mechanisms remain unknown. The present study used high-fat diets combined with low-dose streptozotocin to induce a diabetic liver injury model in T2DM rats to investigate whether AS-IV could alleviate diabetic liver injury and to identify its underlying mechanisms. The results demonstrated that AS-IV treatment could restore changes in food intake, water intake, urine volume and body weight, as well as improve liver function and glucose homeostasis in T2DM rats. Moreover, AS-IV treatment promoted suppressed autophagy in the liver of T2DM rats and improved IR, dyslipidaemia, oxidative stress and inflammation. In addition, AS-IV activated adenosine monophosphate-activated protein kinase (AMPK), which inhibited mTOR. Taken together, the present study suggested that AS-IV alleviated diabetic liver injury in T2DM rats, and its mechanism may be associated with the promotion of AMPK/mTOR-mediated autophagy, which further improved IR, dyslipidaemia, oxidative stress and inflammation. Thus, the regulation of autophagy may be an effective strategy to treat diabetic liver injury in T2DM.
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Affiliation(s)
- Yunfeng Zhu
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yong Su
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jie Zhang
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yanhua Zhang
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yan Li
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yuli Han
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Xianan Dong
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Weizu Li
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Weiping Li
- Key Laboratory of Anti‑Inflammatory and Immunopharmacology, Ministry of Education, Department of Pharmacology, Basic Medicine College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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26
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Casin KM, Calvert JW. Harnessing the Benefits of Endogenous Hydrogen Sulfide to Reduce Cardiovascular Disease. Antioxidants (Basel) 2021; 10:antiox10030383. [PMID: 33806545 PMCID: PMC8000539 DOI: 10.3390/antiox10030383] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 02/02/2023] Open
Abstract
Cardiovascular disease is the leading cause of death in the U.S. While various studies have shown the beneficial impact of exogenous hydrogen sulfide (H2S)-releasing drugs, few have demonstrated the influence of endogenous H2S production. Modulating the predominant enzymatic sources of H2S-cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase-is an emerging and promising research area. This review frames the discussion of harnessing endogenous H2S within the context of a non-ischemic form of cardiomyopathy, termed diabetic cardiomyopathy, and heart failure. Also, we examine the current literature around therapeutic interventions, such as intermittent fasting and exercise, that stimulate H2S production.
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27
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Haye A, Ansari MA, Rahman SO, Shamsi Y, Ahmed D, Sharma M. Role of AMP-activated protein kinase on cardio-metabolic abnormalities in the development of diabetic cardiomyopathy: A molecular landscape. Eur J Pharmacol 2020; 888:173376. [PMID: 32810493 DOI: 10.1016/j.ejphar.2020.173376] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 12/13/2022]
Abstract
Cardiovascular complications associated with diabetes mellitus remains a leading cause of morbidity and mortality across the world. Diabetic cardiomyopathy is a descriptive pathology that in absence of co-morbidities such as hypertension, dyslipidemia initially characterized by cardiac stiffness, myocardial fibrosis, ventricular hypertrophy, and remodeling. These abnormalities further contribute to diastolic dysfunctions followed by systolic dysfunctions and eventually results in clinical heart failure (HF). The clinical outcomes associated with HF are considerably worse in patients with diabetes. The complexity of the pathogenesis and clinical features of diabetic cardiomyopathy raises serious questions in developing a therapeutic strategy to manage cardio-metabolic abnormalities. Despite extensive research in the past decade the compelling approaches to manage and treat diabetic cardiomyopathy are limited. AMP-Activated Protein Kinase (AMPK), a serine-threonine kinase, often referred to as cellular "metabolic master switch". During the development and progression of diabetic cardiomyopathy, a plethora of evidence demonstrate the beneficial role of AMPK on cardio-metabolic abnormalities including altered substrate utilization, impaired cardiac insulin metabolic signaling, mitochondrial dysfunction and oxidative stress, myocardial inflammation, increased accumulation of advanced glycation end-products, impaired cardiac calcium handling, maladaptive activation of the renin-angiotensin-aldosterone system, endoplasmic reticulum stress, myocardial fibrosis, ventricular hypertrophy, cardiac apoptosis, and impaired autophagy. Therefore, in this review, we have summarized the findings from pre-clinical and clinical studies and provided a collective overview of the pathophysiological mechanism and the regulatory role of AMPK on cardio-metabolic abnormalities during the development of diabetic cardiomyopathy.
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Affiliation(s)
- Abdul Haye
- Pharmaceutical Medicine, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohd Asif Ansari
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Syed Obaidur Rahman
- Pharmaceutical Medicine, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Yasmeen Shamsi
- Department of Moalejat, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Danish Ahmed
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture Technology and Sciences, Allahabad, Uttar Pradesh, India
| | - Manju Sharma
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
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28
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Piragine E, Calderone V. Pharmacological modulation of the hydrogen sulfide (H 2 S) system by dietary H 2 S-donors: A novel promising strategy in the prevention and treatment of type 2 diabetes mellitus. Phytother Res 2020; 35:1817-1846. [PMID: 33118671 DOI: 10.1002/ptr.6923] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/15/2020] [Accepted: 10/06/2020] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus (T2DM) represents the most common age-related metabolic disorder, and its management is becoming both a health and economic issue worldwide. Moreover, chronic hyperglycemia represents one of the main risk factors for cardiovascular complications. In the last years, the emerging evidence about the role of the endogenous gasotransmitter hydrogen sulfide (H2 S) in the pathogenesis and progression of T2DM led to increasing interest in the pharmacological modulation of endogenous "H2 S-system". Indeed, H2 S directly contributes to the homeostatic maintenance of blood glucose levels; moreover, it improves impaired angiogenesis and endothelial dysfunction under hyperglycemic conditions. Moreover, H2 S promotes significant antioxidant, anti-inflammatory, and antiapoptotic effects, thus preventing hyperglycemia-induced vascular damage, diabetic nephropathy, and cardiomyopathy. Therefore, H2 S-releasing molecules represent a promising strategy in both clinical management of T2DM and prevention of macro- and micro-vascular complications associated to hyperglycemia. Recently, growing attention has been focused on dietary organosulfur compounds. Among them, garlic polysulfides and isothiocyanates deriving from Brassicaceae have been recognized as H2 S-donors of great pharmacological and nutraceutical interest. Therefore, a better understanding of the therapeutic potential of naturally occurring H2 S-donors may pave the way to a more rational use of these nutraceuticals in the modulation of H2 S homeostasis in T2DM.
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Affiliation(s)
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy.,Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, Pisa, Italy
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Luo W, Gui DD, Yan BJ, Ren Z, Peng LJ, Wei DH, Liu LS, Zhang DW, Jiang ZS. Hydrogen Sulfide Switch Phenomenon Regulating Autophagy in Cardiovascular Diseases. Cardiovasc Drugs Ther 2020; 34:113-121. [PMID: 32090295 DOI: 10.1007/s10557-019-06927-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hydrogen sulfide (H2S), a novel gaseous signaling molecule, is a vital physiological signal in mammals. H2S protects the cardiovascular system via modulation of vasodilation, vascular remodeling, and inhibition of vascular calcification, and also has anti-atherosclerosis properties. Autophagy is a lysosomal-mediated intracellular degradation mechanism for excessive or abnormal proteins and lipids. The contribution of autophagy to normal and disease-state cell physiology is extremely complicated. Autophagy acts as a double-edged sword in the cardiovascular system. It can defend against damage to cells caused by environmental changes and it can also induce active cell death under certain conditions. In recent years, accumulating evidence indicates that H2S can up- or downregulate autophagy in many pathological processes, thereby switching from a harmful to a beneficial role. In this review, we summarize progress on understanding the mechanism by which H2S regulates autophagy in cardiovascular disease. We also discuss a H2S switch phenomenon that regulates autophagy and provides protection in cardiovascular diseases.
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Affiliation(s)
- Wen Luo
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China
| | - Dan-Dan Gui
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China
| | - Bin-Jie Yan
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China
| | - Li-Jun Peng
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China.,Medical Record Statistics Office and Library, The Pediatric Academy of University of South China, Changsha, 410007, Hunan Province, China
| | - Dang-Heng Wei
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China
| | - Lu-Shan Liu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
| | - Zhi-Sheng Jiang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, Hunan Province, China.
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30
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Zhang J, Ye J, Yuan C, Fu Q, Zhang F, Zhu X, Wang L, Gao P, Shu G, Wang S, Liu Q, Jiang Q. Hydrogen sulfide is a regulator of mammary gland development in prepubescent female mice. Mol Med Rep 2020; 22:4061-4069. [PMID: 33000185 DOI: 10.3892/mmr.2020.11462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 07/09/2020] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effects of exogenous H2S on mammary gland development in pubescent mice and to explore the underlying mechanism. The mouse mammary epithelial cell line HC11, along with C57BL/6J mice, were treated with different concentrations of sodium hydrosulfide (NaHS), which is a donor of H2S. The HC11 cell viability, pubescent mammary gland development, and the involvement of proliferative proteins and pathways were assessed by CCK‑8 assay, EdU assay, whole mount staining, H&E staining, western blotting and reverse transcription‑quantitative PCR. Both in vitro and in vivo, a low concentration of NaHS (100 µM in vitro; 9 mg/kg in vivo) significantly promoted the viability of HC11 cells and the development of mammary glands by increasing the expression of the proliferative markers cyclin D1/3 and proliferating cell nuclear antigen. However, a high concentration of NaHS (1,000 µM in vitro; 18 mg/kg in vivo) inhibited HC11 cell viability, mammary gland development and the expression levels of proteins involved in proliferation. Subsequent experiments revealed that NaHS regulated the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt)‑mammalian target of rapamycin (mTOR) signaling pathway during this process. In vivo, intraperitoneal injection of low concentration NaHS (9 mg/kg) activated the PI3K/Akt‑mTOR pathway in mammary glands of pubescent mice, increased the secretion of insulin‑like growth factor 1 (IGF‑1) and estradiol (E2), and then stimulated mammary gland ductal development. Whereas a high concentration of NaHS (18 mg/kg) elicited the opposite effects to those of low‑dose NaHS. In conclusion, the present study demonstrated that exogenous H2S supplied by NaHS may exert bidirectional effects on mammary gland ductal development; promoting ductal development at a low concentration and inhibiting it at a high concentration. The effects of H2S may occur via the intracellular PI3K/Akt‑mTOR signaling pathway, or by regulation of the secretion of IGF‑1 and E2.
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Affiliation(s)
- Jing Zhang
- College of Animal Science, Shanxi Agricultural University, Jinzhong, Shanxi 030801, P.R. China
| | - Jiayi Ye
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Cong Yuan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Qin Fu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Fenglin Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Xiaotong Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
| | - Qiang Liu
- College of Animal Science, Shanxi Agricultural University, Jinzhong, Shanxi 030801, P.R. China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
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31
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Testai L, Citi V, Martelli A, Brogi S, Calderone V. Role of hydrogen sulfide in cardiovascular ageing. Pharmacol Res 2020; 160:105125. [PMID: 32783975 DOI: 10.1016/j.phrs.2020.105125] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/17/2020] [Accepted: 08/05/2020] [Indexed: 12/11/2022]
Abstract
Cardiovascular diseases are the main cause of morbidity and mortality in the Western society and ageing is a relevant non-modifiable risk factor. Morphological and functional alterations at endothelial level represent first events of ageing, inevitably followed by vascular dysfunction and consequent atherosclerosis that deeply influences cardiovascular health. Indeed, myocardial hypertrophy and fibrosis typically occur and contribute to compromise overall cardiac output. As regards the intracellular molecular mechanisms involved in the cardiovascular ageing, an intricate network is emerging, revealing a role for many mediators, including SIRT1/AMPK/PCG1α pathway, anti-oxidants factors (i.e. Nrf-2 and FOXOs) and pro-inflammatory cytokines. Thus, the search for pharmacological and non-pharmacological strategies that can promote a "healthy ageing", in order to slow down age-related machinery, are currently an exciting challenge for the biomedical research. Interestingly, hydrogen sulfide (H2S) has been recently recognized as a new player capable to influence intracellular machinery involved in ageing and then it is view as a potential target for preventing cardiovascular diseases. Therefore, this review is focused on the role of H2S in cardiovascular ageing, and on the evidence of the relationship between progressive decline in endogenous H2S levels and the onset of various cardiovascular age-related diseases.
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Affiliation(s)
- Lara Testai
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120, Pisa, Italy; Interdepartmental Research Centre of Ageing, Biology and Pathology, University of Pisa, 56120, Pisa, Italy; Interdepartmental Research Centre "Nutraceuticals and Food for Health (NUTRAFOOD)", University of Pisa, 56120, Pisa, Italy.
| | - Valentina Citi
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120, Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120, Pisa, Italy; Interdepartmental Research Centre of Ageing, Biology and Pathology, University of Pisa, 56120, Pisa, Italy; Interdepartmental Research Centre "Nutraceuticals and Food for Health (NUTRAFOOD)", University of Pisa, 56120, Pisa, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120, Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120, Pisa, Italy; Interdepartmental Research Centre of Ageing, Biology and Pathology, University of Pisa, 56120, Pisa, Italy; Interdepartmental Research Centre "Nutraceuticals and Food for Health (NUTRAFOOD)", University of Pisa, 56120, Pisa, Italy
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Camara R, Matei N, Camara J, Enkhjargal B, Tang J, Zhang JH. Hydrogen gas therapy improves survival rate and neurological deficits in subarachnoid hemorrhage rats: a pilot study. Med Gas Res 2020; 9:74-79. [PMID: 31249255 PMCID: PMC6607870 DOI: 10.4103/2045-9912.260648] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The high morbidity, high mortality, and significant shortage of effective therapies for subarachnoid hemorrhage (SAH) have created an urgency to discover novel therapies. Human studies in Asia have established the safety of hydrogen gas in the treatment of hepatic, renal, pulmonary, and cardiac diseases. Mechanistically, hydrogen gas has been shown to affect oxidative stress, inflammation, and apoptosis. We hypothesized that hydrogen therapy would improve neurological function and increase survival rate in SAH. High dose hydrogen gas (66% at 3 L/min) was administered for 2 hours at 0.5, 8, and 18 hours after SAH. This treatment increased 72-hour survival rate and provided 24-hour neuroprotection after SAH in rats. To our knowledge, this is the first report demonstrating that high dose hydrogen gas therapy reduces mortality and improves outcome after SAH. Our results correlate well with the proposed mechanisms of hydrogen gas therapy within the literature. We outline four pathways and downstream targets of hydrogen gas potentially responsible for our results. A potentially complex network of pathways responsible for the efficacy of hydrogen gas therapy, along with a limited mechanistic understanding of these pathways, justifies further investigation to provide a basis for clinical trials and the advancement of hydrogen gas therapy in humans. This study was approved by the Institutional Animal Care and Use Committee of Loma Linda University, USA (Approval No. 8160016) in May 2016.
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Affiliation(s)
- Richard Camara
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA
| | - Nathanael Matei
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA
| | - Justin Camara
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA
| | - Budbazar Enkhjargal
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA
| | - John H Zhang
- Department of Physiology and Pharmacology; Department of Anesthesiology; Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA
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33
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Hydrogen molecules can modulate enzymatic activity and structural properties of pepsin in vitro. Colloids Surf B Biointerfaces 2020; 189:110856. [DOI: 10.1016/j.colsurfb.2020.110856] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 01/19/2023]
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34
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Zhang Y, Wang Y, Read E, Fu M, Pei Y, Wu L, Wang R, Yang G. Golgi Stress Response, Hydrogen Sulfide Metabolism, and Intracellular Calcium Homeostasis. Antioxid Redox Signal 2020; 32:583-601. [PMID: 31870162 DOI: 10.1089/ars.2019.7824] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Aims: The physiological and pathological importance of hydrogen sulfide (H2S) as a novel gasotransmitter has been widely recognized. Cystathionine gamma-lyase (CSE) is one of the major H2S-producing enzymes and it regulates diverse functions in connection with intracellular calcium (Ca2+). The aim of this study is to examine the role of H2S in Golgi stress-related cell injury and skeletal muscle disorders. Results: Golgi stressors (brefeldin A [BFA] and monensin) decreased the expression of GM130 and ATP2C1 (two markers of Golgi stress response), induced Golgi apparatus fragmentation, and caused a higher level of oxidative stress and cell apoptosis in mouse myoblast cells. In addition, Golgi stressors upregulated CSE expression and endogenous H2S generation, and exogenously applied H2S was able to protect but inhibition of CSE/H2S system deteriorated Golgi stress response. Activating transcription factor 4 (ATF4) acted as an upstream molecule to increase CSE expression on Golgi stress response. Mechanically, Golgi stressors induced intracellular level of Ca2+, and chelating cellular Ca2+ markedly attenuated Golgi stress response, indicating the key role of Ca2+ in initiating Golgi stress and cell apoptosis. Further, administration of either angiotensin II or BFA initiated Golgi stress response and induced skeletal muscle atrophy in mice, which was further deteriorated by CSE deficiency but rescued by exogenously applied sodium hydrosulfide (NaHS). Innovation and Conclusion: The activation of the CSE/H2S pathway and the decrease of intracellular Ca2+ are two cellular protective mechanisms against Golgi stress, and the CSE/H2S system would be a target for preventing skeletal muscle dysfunctions.
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Affiliation(s)
- Yanjie Zhang
- School of Life Science, Shanxi University, Taiyuan, China.,Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Yuehong Wang
- Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Ethan Read
- Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Ming Fu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.,School of Human Kinetics, Laurentian University, Sudbury, Canada.,Health Sciences North Research Institute, Sudbury, Canada
| | - Yanxi Pei
- School of Life Science, Shanxi University, Taiyuan, China
| | - Lingyun Wu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.,School of Human Kinetics, Laurentian University, Sudbury, Canada.,Health Sciences North Research Institute, Sudbury, Canada
| | - Rui Wang
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Guangdong Yang
- Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
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Hydrogen Sulfide as a Potential Alternative for the Treatment of Myocardial Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4105382. [PMID: 32064023 PMCID: PMC6998763 DOI: 10.1155/2020/4105382] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022]
Abstract
Harmful, stressful conditions or events in the cardiovascular system result in cellular damage, inflammation, and fibrosis. Currently, there is no targeted therapy for myocardial fibrosis, which is highly associated with a large number of cardiovascular diseases and can lead to fatal heart failure. Hydrogen sulfide (H2S) is an endogenous gasotransmitter similar to nitric oxide and carbon monoxide. H2S is involved in the suppression of oxidative stress, inflammation, and cellular death in the cardiovascular system. The level of H2S in the body can be boosted by stimulating its synthesis or supplying it exogenously with a simple H2S donor with a rapid- or slow-releasing mode, an organosulfur compound, or a hybrid with known drugs (e.g., aspirin). Hypertension, myocardial infarction, and inflammation are exaggerated when H2S is reduced. In addition, the exogenous delivery of H2S mitigates myocardial fibrosis caused by various pathological conditions, such as a myocardial infarct, hypertension, diabetes, or excessive β-adrenergic stimulation, via its involvement in a variety of signaling pathways. Numerous experimental findings suggest that H2S may work as a potential alternative for the management of myocardial fibrosis. In this review, the antifibrosis role of H2S is briefly addressed in order to gain insight into the development of novel strategies for the treatment of myocardial fibrosis.
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Zhao X, Su L, He X, Zhao B, Miao J. Long noncoding RNA CA7-4 promotes autophagy and apoptosis via sponging MIR877-3P and MIR5680 in high glucose-induced vascular endothelial cells. Autophagy 2020; 16:70-85. [PMID: 30957640 PMCID: PMC6984615 DOI: 10.1080/15548627.2019.1598750] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/03/2019] [Accepted: 03/15/2019] [Indexed: 01/08/2023] Open
Abstract
Vascular endothelial cells (VECs) that form the inner wall of blood vessels can be injured by high glucose-induced autophagy and apoptosis. Although the role of long noncoding RNA in regulating cell fate has received widespread attention, long noncoding RNAs (lncRNAs) that can both regulate autophagy and apoptosis need to be discovered. In this study, we identified that a small chemical molecule, 3-benzyl-5-([2-nitrophenoxy] methyl)-dihydrofuran-2(3H)-one (3BDO), synthesized by us, could inhibit VEC autophagy and apoptosis induced by a high concentration of glucose. To find new lncRNAs that regulate autophagy and apoptosis in VECs, we performed lncRNA microarray analysis. We found and verified an upregulated lncRNA named CA7-4 that was induced by a high concentration of glucose could be downregulated by 3BDO most obviously among all of the detected lncRNAs. Meanwhile, we investigated the mechanism of CA7-4 in regulating VEC autophagy and apoptosis. The results showed that CA7-4 facilitated endothelial autophagy and apoptosis as a competing endogenous RNA (ceRNA) by decoying MIR877-3P and MIR5680. Further study elucidated that MIR877-3P could trigger the decrease of CTNNBIP1 (catenin beta interacting protein 1) by combining with its 3' UTR and then upregulating CTNNB1 (catenin beta 1); MIR5680 inhibited the phosphorylation of AMP-activated protein kinase (AMPK) by targeting and decreasing DPP4 (dipeptidyl peptidase 4). Therefore, CA7-4, MIR877-3P and MIR5680 represent new signal pathways that regulate VEC autophagy and apoptosis under the high-glucose condition.Abbreviations: 3BDO: 3-benzyl-5-([2-nitrophenoxy] methyl)-dihydrofuran-2(3H)-one; 3' UTR: 3' untranslated region; AGO2: argonaute RISC catalytic component 2; AMPK: AMP-activated protein kinase/protein kinase AMP-activated; BAX/BCL2L4: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; CASP3: caspase 3; ceRNA: competing endogenous RNA; CTNNB1: catenin beta 1; CTNNBIP1/ICAT: catenin beta interacting protein 1; DPP4: dipeptidyl peptidase 4; FGF2/FGF-2: fibroblast growth factor 2; HG: high concentration glucose (30 mM glucose); lncRNA: long noncoding RNA; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; miRNA: microRNA; MIR4778-3P: microRNA 4778-3p; MIR561-3P: microRNA 561-3p; MIR5680: microRNA 5680; MIR877-3P: microRNA 877-3p; MTOR: mechanistic target of rapamycin kinase; Mut: mutant; NC: negative control; NG: normal concentration glucose (5.5 mM glucose); PARP1: poly(ADP-ribose) polymerase 1; qPCR: quantitative real-time PCR; RNA-FISH: RNA-fluorescence in situ hybridization; ROS: reactive oxygen species; RT-PCR: reverse transcription polymerase chain reaction; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TGFB2-OT1: TGFB2 overlapping transcript 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VECs: vascular endothelial cells; WT: wild type.
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Affiliation(s)
- Xuan Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, P. R. China
| | - Le Su
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, P. R. China
| | - Xiaoying He
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, P. R. China
| | - Baoxiang Zhao
- Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan, P. R. China
| | - Junying Miao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, P. R. China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, P. R. China
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Luo J, Yan D, Li S, Liu S, Zeng F, Cheung CW, Liu H, Irwin MG, Huang H, Xia Z. Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats. J Cell Mol Med 2019; 24:1760-1773. [PMID: 31856386 PMCID: PMC6991641 DOI: 10.1111/jcmm.14870] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 10/15/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022] Open
Abstract
Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) following the disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over‐activation and consequently attenuate DCM. Streptozotocin‐induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure‐volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15‐F2t‐Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme‐linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT‐PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end‐systolic volume (LVVs) as compared to non‐diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P < .05). Hearts of diabetic rats displayed excessive oxidative stress manifested as increased levels of 15‐F2t‐Isoprostane and superoxide anion production, increased apoptotic cell death and cardiomyocytes autophagy that were concomitant with reduced expressions of Nrf2, heme oxygenase‐1 (HO‐1) and Keap1. ALP reverted all the above‐mentioned diabetes‐induced biochemical changes except that it did not affect the levels of Keap1. In vitro, ALP increased Nrf2 and reduced the hyperglycaemia‐induced increases of H9C2 cardiomyocyte hypertrophy, oxidative stress, apoptosis and autophagy, and enhanced cellular viability. Nrf2 gene silence cancelled these protective effects of ALP in H9C2 cells. Activation of Nrf2 subsequent to the suppression of Keap1 and the mitigation of autophagy over‐activation may represent major mechanisms whereby ALP attenuates DCM.
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Affiliation(s)
- Jierong Luo
- Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Dan Yan
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Sisi Li
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Shiming Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fei Zeng
- Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Chi Wai Cheung
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Hong Liu
- Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, CA, USA
| | - Michael G Irwin
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Huansen Huang
- Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhengyuan Xia
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
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38
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Li J, Yuan YQ, Zhang L, Zhang H, Zhang SW, Zhang Y, Xuan XX, Wang MJ, Zhang JY. Exogenous hydrogen sulfide protects against high glucose-induced apoptosis and oxidative stress by inhibiting the STAT3/HIF-1α pathway in H9c2 cardiomyocytes. Exp Ther Med 2019; 18:3948-3958. [PMID: 31616516 PMCID: PMC6781810 DOI: 10.3892/etm.2019.8036] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 06/20/2019] [Indexed: 02/07/2023] Open
Abstract
Hydrogen sulfide (H2S), an endogenous gasotransmitter, possesses multiple physiological and pharmacological properties including anti-apoptotic, anti-oxidative stress and cardiac protective activities in diabetic cardiomyopathy. An increasing body of evidence has suggested that signal transducer and activator of transcription 3 (STAT3) has beneficial effects in the heart. However, the effect of diabetes on the phosphorylation or activation of cardiac STAT3 appears to be controversial. The present study was designed to investigate the precise function of the STAT3/hypoxia-inducible factor-1α (HIF-1α) signaling pathway in high glucose (HG)-induced H9c2 cardiomyocyte injury and the function of the STAT3/HIF-1α pathway in the cardioprotective action of H2S. The results revealed that GYY4137 pretreatment substantially ameliorated the HG-induced decrease in cell viability and the increase in lactate dehydrogenase (LDH) release in H9c2 cells. Additionally, HG treatment resulted in the upregulation of the phosphorylated (p)-STAT3/STAT3 ratio and HIF-1α protein expression in H9c2 cells, indicating that the activation of the STAT3/HIF-1α pathway was induced by HG. STAT3/HIF-1α pathway inhibition induced by transfection with STAT3 small interfering (si)-RNA attenuated the HG-induced downregulation of cell viability and the upregulation of LDH release. Furthermore, STAT3 siRNA transfection and GYY4137 pretreatment combined attenuated HG-induced apoptosis as illustrated by the decrease in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, caspase-3 activity, apoptosis ratio and BCL2 associated X, apoptosis regulator/BCL2 apoptosis regulator ratio in H9c2 cells. In addition, STAT3 siRNA transfection and GYY4137 blocked HG-induced oxidative stress as evidenced by the decrease in reactive oxygen species generation, malondialdehyde content and NADPH oxidase 2 expression, and the increase in superoxide dismutase activity and glutathione level. Notably, GYY4137 pretreatment was revealed to reduce the p-STAT3/STAT3 ratio and HIF-1α protein expression, resulting in the inhibition of the STAT3/HIF-1α signaling pathway in HG-treated H9c2 cells. Altogether, the present results demonstrated that H2S mitigates HG-induced H9c2 cell damage, and reduces apoptosis and oxidative stress by suppressing the STAT3/HIF-1α signaling pathway.
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Affiliation(s)
- Jing Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Yi-Qiang Yuan
- Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, Henan 450016, P.R. China
| | - Li Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Hua Zhang
- Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, Henan 450016, P.R. China
| | - Shen-Wei Zhang
- Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, Henan 450016, P.R. China
| | - Yu Zhang
- Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, Henan 450016, P.R. China
| | - Xue-Xi Xuan
- Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, Henan 450016, P.R. China
| | - Ming-Jie Wang
- Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, Henan 450016, P.R. China
| | - Jin-Ying Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
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Hao Y, Wang W, Wu D, Liu K, Sun Y. Retracted: Bilobalide alleviates tumor necrosis factor‐alpha‐induced pancreatic beta‐cell MIN6 apoptosis and dysfunction through upregulation of miR‐153. Phytother Res 2019; 34:409-417. [PMID: 31667906 DOI: 10.1002/ptr.6533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/22/2019] [Accepted: 10/09/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Yan Hao
- Department of EndocrinologyJining No.1 People's Hospital Jining China
| | - Weiwei Wang
- Department of EndocrinologyJining No.1 People's Hospital Jining China
| | - Dong Wu
- Emergency DepartmentJining No.1 People's Hospital Jining China
| | - Kai Liu
- Emergency DepartmentJinxiang People's Hospital Jining China
| | - Yihan Sun
- Department of EndocrinologyJining No.1 People's Hospital Jining China
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40
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Yin C, Ke X, Zhang R, Hou J, Dong Z, Wang F, Zhang K, Zhong X, Yang L, Cui H. G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR. FASEB J 2019; 33:14036-14050. [PMID: 31647887 DOI: 10.1096/fj.201900233rr] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
As an important methyltransferase, G9a has been reported to be abnormally expressed in various human cancers and plays essential roles in tumorigenesis. However, the biologic functions and molecular mechanisms of G9a in gastric cancer (GC) remain unclear. GC is the fifth most frequent cancer around the world and seriously threatens human health, especially in developing countries. Here, our results showed that high expression of G9a was intensively correlated with poor prognosis and more advanced stages of GCs. Knockdown of G9a or treatment with its inhibitor, BIX01294, significantly reduced cell growth by cell cycle arrest and autophagy. In addition, the mechanistic target of rapamycin (mTOR) was evidently decreased after G9a silencing or inhibition, and mTOR activation partially rescued the effects of cell proliferation inhibition and autophagy induced by G9a knockdown or inhibition. Down-regulation of G9a effectively inhibited mTOR expression and tumor growth in the xenograft tumor model of GC cells. We also showed that G9a regulates mTOR and cell proliferation and autophagy depending on its histone methylase activity. Using chromatin immunoprecipitation analysis, we found that mTOR expression was associated with promoter methylation and an enrichment for mono- and dimethylated histone 3 lys 9 (H3K9). G9a knockdown revealed an apparent decrease in H3K9 monomethylation levels, but no apparent change in H3K9 dimethylation levels at the mTOR promoter. These results indicate that G9a is a novel and promising therapeutic target for GC treatment.-Yin, C., Ke, X., Zhang, R., Hou, J., Dong, Z., Wang, F., Zhang, K., Zhong, X., Yang, L., Cui, H. G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR.
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Affiliation(s)
- Chao Yin
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Xiaoxue Ke
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Rui Zhang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jianbing Hou
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Feng Wang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Kui Zhang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Xi Zhong
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
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41
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Kourounakis AP, Xanthopoulos D, Tzara A. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med Res Rev 2019; 40:709-752. [PMID: 31512284 DOI: 10.1002/med.21634] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/22/2019] [Accepted: 08/21/2019] [Indexed: 12/15/2022]
Abstract
Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active-site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug-like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.
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Affiliation(s)
- Angeliki P Kourounakis
- Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Xanthopoulos
- Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Ariadni Tzara
- Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
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42
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Wu L, Chen Y, Wang CY, Tang YY, Huang HL, Kang X, Li X, Xie YR, Tang XQ. Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1. Front Mol Neurosci 2019; 12:194. [PMID: 31481873 PMCID: PMC6710442 DOI: 10.3389/fnmol.2019.00194] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 07/25/2019] [Indexed: 01/31/2023] Open
Abstract
Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H2S) is a novel neuroprotectant. The present work was to investigate the potential effect of H2S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H2S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16INK4a and p21CIP1. NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H2S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H2S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H2S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H2S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.
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Affiliation(s)
- Lei Wu
- Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Ying Chen
- Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China.,Department of Pharmacology, The Central Hospital of Hengyang, Hengyang, China
| | - Chun-Yan Wang
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Yi-Yun Tang
- Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, China
| | - Hong-Lin Huang
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Xuan Kang
- Institute of Neurology, the First Affiliated Hospital, University of South China, Hengyang, China
| | - Xiang Li
- Institute of Neurology, the First Affiliated Hospital, University of South China, Hengyang, China
| | - Yu-Rong Xie
- College of Chemistry and Chemical Engineering, University of South China, Hengyang, China
| | - Xiao-Qing Tang
- Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China.,Institute of Neurology, the First Affiliated Hospital, University of South China, Hengyang, China
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H 2S attenuates endoplasmic reticulum stress in hypoxia-induced pulmonary artery hypertension. Biosci Rep 2019; 39:BSR20190304. [PMID: 31239370 PMCID: PMC6614575 DOI: 10.1042/bsr20190304] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 06/11/2019] [Accepted: 06/20/2019] [Indexed: 01/07/2023] Open
Abstract
Background: Previous studies have found that hydrogen sulfide (H2S) has multiple functions such as anti-inflammatory, antioxidative in addition to biological effects among the various organs. Exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is a key component of vascular remodeling. We hypothesized that endogenous bioactive molecular known to suppress endoplasmic reticulum (ER) stress signaling, like H2S, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension (PAH). Methods and results: A hypoxic model was established with PASMCs to investigate the possible role of H2S in PAH. Effects of H2S on proliferation of PASMCs were evaluated by CCK-8 and EdU assay treated with or without GYY4137 (donor of H2S). H2S significantly inhibited hypoxia-induced increase in PASMCs proliferation in a dose-dependent manner. H2S by intraperitoneal injection with rats both prevented and reversed chronic hypoxia-induced pulmonary hypertension in rats, decreasing pulmonary vascular resistance, pulmonary artery remodeling and right ventricular hypertrophy, and improving functional capacity without affecting systemic hemodynamic. Exogenous H2S suppressed ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation, and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. Conclusion: H2S effectively inhibits hypoxia-induced increase in cell proliferation, migration, and oxidative stress in PASMCs, and NOX-4 might be the underlying mechanism of PAH. Attenuating ER stress with exogenous H2S may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.
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Xia YQ, Ning JZ, Cheng F, Yu WM, Rao T, Ruan Y, Yuan R, Du Y. GYY4137 a H 2S donor, attenuates ipsilateral epididymis injury in experimentally varicocele-induced rats via activation of the PI3K/Akt pathway. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2019; 22:729-735. [PMID: 32373293 PMCID: PMC7196355 DOI: 10.22038/ijbms.2019.30588.7372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVES The current study was aimed to investigate the effect of morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate (GYY4137) on ipsilateral epididymis injury in a rat model of experimental varicocele (VC). MATERIALS AND METHODS Sixty Wistar rats were randomly assigned to sham, sham plus GYY4137, VC and VC plus GYY4137 groups. Sperm quality parameters, including sperm count, motility and viability were evaluated after 4 weeks. Histological changes were measured by hematoxylin and eosin staining between the groups. The oxidative stress levels were estimated by determining epididymal superoxide dismutase (SOD) and malondialdehyde (MDA). The apoptosis status and the expression of phosphatidylinositol 3'-OH kinase (PI3K)/Akt were analyzed by immunohistochemical analysis, western blot and RT-qPCR. RESULTS VC resulted in the decrease of sperm parameters, significant histological damage and higher levels of oxidative stress and apoptosis. Compared to the VC group, GYY4137 markedly ameliorated these observed changes. In addition, treatment with GYY4137 obviously reduced the levels of caspase-3 and Bax and increased the levels of the phosphorylation of PI3K p85 and Akt. CONCLUSION Our data demonstrated that GYY4137 may alleviate the sperm damage and epididymis injury in experimentally VC-induced rats by activation of the PI3K/Akt pathway.
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Affiliation(s)
- Yu-Qi Xia
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jin-Zhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei-Min Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yuan Ruan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Run Yuan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yang Du
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Liu W, Wang Z, Xia Y, Kuang H, Liu S, Li L, Tang C, Yin D. The balance of apoptosis and autophagy via regulation of the AMPK signal pathway in aging rat striatum during regular aerobic exercise. Exp Gerontol 2019; 124:110647. [PMID: 31255733 DOI: 10.1016/j.exger.2019.110647] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/28/2022]
Abstract
The objective was to analyze the effects of aerobic exercise on aging striatum stress resistance, and the adaptive mechanisms related to neurodegenerative diseases, and the occurrence, and development of neural degeneration. The 10-weeks of regular moderate-intensity aerobic exercise intervention were carried out in the aerobic exercise runner Sprague-Dawley rats. Apoptotic nuclei appeared in the striatum of aged rats, showing a tendency to relate to aging. The apoptotic index of the striatum in young, middle-aged, and old-aged rats of the aerobic exercise groups increased by 205.56%, 57%, and 68.24%. Autophagy markers Beclin l and LC 3-II expression, AMPKα1 and pAMPKα1 expression increased significantly in all age-exercise groups. The ratio of AMPKα1/pAMPKα1 increased after exercise, and the tendency of exercise to alter autophagy and cell apoptosis increased with aging. Then SirT2 mRNA was significantly upregulated in the aerobic exercise runner groups. In conclusion, we showed that the balance of autophagy and apoptosis were closely regulated by regular aerobic exercise, which affected the development of aging, and via regulation of the AMPK/SirT2 signaling pathway.
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Affiliation(s)
- Wenfeng Liu
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Zhiyuan Wang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China
| | - Yan Xia
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China
| | - Heyu Kuang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China
| | - Shaopeng Liu
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China
| | - Li Li
- School of Health & Kinesiology, Georgia Southern University, Statesboro, GA 30460, USA
| | - Changfa Tang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China.
| | - Dazhong Yin
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, Hunan 410012, China; Qingyuan People's Hospital, the Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511500, China.
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Endogenous CSE/Hydrogen Sulfide System Regulates the Effects of Glucocorticoids and Insulin on Muscle Protein Synthesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9752698. [PMID: 31089421 PMCID: PMC6476024 DOI: 10.1155/2019/9752698] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/09/2018] [Accepted: 12/18/2018] [Indexed: 01/25/2023]
Abstract
Aims Insulin and glucocorticoids play crucial roles in skeletal muscle protein turnover. Fast-twitch glycolytic fibres are more susceptible to atrophy than slow-twitch oxidative fibres. Based on accumulating evidence, hydrogen sulfide (H2S) is a physiological mediator of this process. The regulatory effect of H2S on protein synthesis in fast-twitch fibres was evaluated. Results A NaHS (sodium hydrosulfide) injection simultaneously increased the diameter of M. pectoralis major (i.e., fast-twitch glycolytic fibres) and activated the mammalian target of the rapamycin (mTOR)/p70S6 kinase (p70S6K) pathway. Dexamethasone (DEX) inhibited protein synthesis, downregulated mTOR and p70S6K phosphorylation, and suppressed the expression of the cystathionine γ-lyase (CSE) protein in myoblasts. The precursor of H2S, L-cysteine, completely abolished the inhibitory effects of DEX. The CSE inhibitor DL-propargylglycine (PAG) completely abrogated the effects of RU486 on blocking the suppressive effects of DEX. The H2S donor NaHS increased the H2S concentrations and abrogated the inhibitory effects of DEX on protein synthesis. Insulin increased protein synthesis and upregulated CSE expression. However, PAG abrogated the stimulatory effects of insulin on protein synthesis and the activity of the mTOR/p70S6K pathway. Innovation These results demonstrated that CSE/H2S regulated protein synthesis in fast-twitch muscle fibres, and glucocorticoids and insulin regulated protein synthesis in an endogenous CSE/H2S system-dependent manner. Conclusions The results from the present study suggest that the endogenous CSE/H2S system regulates fast-twitch glycolytic muscle degeneration and regeneration.
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Wang J, Wu D, Wang H. Hydrogen sulfide plays an important protective role by influencing autophagy in diseases. Physiol Res 2019; 68:335-345. [PMID: 30904008 DOI: 10.33549/physiolres.933996] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Autophagy can regulate cell growth, proliferation, and stability of cell environment. Its dysfunction can be involved in a variety of diseases. Hydrogen sulfide (H(2)S) is an important signaling molecule that regulates many physiological and pathological processes. Recent studies indicate that H(2)S plays an important protective role in many diseases through influencing autophagy, but its mechanism is not fully understood. This article reviewed the progress about the effect of H(2)S on autophagy in diseases in recent years in order to provide theoretical basis for the further research on the interaction of H(2)S and autophagy and the mechanisms involved.
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Affiliation(s)
- J Wang
- School of Basic Medical Science, Henan University, Kaifeng, Henan, China.
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Mao Z, Yao M, Li Y, Fu Z, Li S, Zhang L, Zhou Z, Tang Q, Han X, Xia Y. miR-96-5p and miR-101-3p as potential intervention targets to rescue TiO 2 NP-induced autophagy and migration impairment of human trophoblastic cells. Biomater Sci 2018; 6:3273-3283. [PMID: 30345998 DOI: 10.1039/c8bm00856f] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Autophagy induced by titanium dioxide nanoparticles (TiO2 NPs) has been realized nowadays, but the underlying mechanisms remain largely unknown. Animal studies have confirmed that autophagy might be an important mechanism to impair placenta development, but the reversal of damage is not clear. Here, we used human HTR-8/SVneo (HTR) cells as a proper model to explore how autophagy is regulated in TiO2 NP-exposed human placenta cells. Our studies showed that TiO2 NPs could enter HTR cells and locate in cytoplasm. Although they did not affect cell viability even under 100 μg ml-1, autophagy was observed and cell migration ability was severely impaired. Further study showed that TiO2 NPs increased the expressions of both miR-96-5p and miR-101-3p and then, they targeted mTOR and decreased the expression of mTOR proteins. In addition, miR-96-5p also targeted Bcl-2 to down-regulate Bcl-2 protein level, which is also a key regulator of autophagy. We proved that when two microRNA inhibitors were added, cell autophagy was, to a greater extent, reversed compared with the result when one inhibitor was added, and the cell migration ability was also reversed to a greater degree. Our studies revealed that TiO2 NPs might impair placenta development via autophagy. Moreover, miR-96-5p as well as miR-101-3p may act as potential targets to reverse TiO2 NP-induced autophagy and placenta dysfunction.
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Affiliation(s)
- Zhilei Mao
- Changzhou Maternity and Child Health Care Hospital affiliated to Nanjing Medical University, Changzhou 213003, Jiangsu, China
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Wu A, Hu P, Lin J, Xia W, Zhang R. Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction. Front Pharmacol 2018; 9:1292. [PMID: 30459625 PMCID: PMC6232417 DOI: 10.3389/fphar.2018.01292] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022] Open
Abstract
Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms. HU308 was used for the selective activation of CB2. Bafilomycin A1 was used for the blockade of autophagy and compound C was used to inhibit AMPK signaling. An streptozotocin (STZ)-induced mice model and high glucose (HG)-challenged cardiomyocytes were applied for study. Cardiac function was detected by echocardiography and Western blot for the detection of autophagy-related and its signaling-related proteins. Transmission electron microscopy was used for the analysis of autophagosome number. Cell viability was detected by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. We found that activating CB2 by HU308 improved cardiac function in DCM as well as cell viability in cardiomyocytes under HG challenge, while the administration of bafilomycin A1 attenuated the protective effects. HU308 enhanced the level of autophagy in the heart tissues from DCM mice as well as cardiomyocytes under HG challenge. HU308 triggered the AMPK-mTOR-p70S6K signaling pathway, while the administration of compound C attenuated the cardio-protective effect of HU308 in cardiomyocytes under HG challenge. In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.
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Affiliation(s)
- Aiping Wu
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
| | - Pengfei Hu
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Jian Lin
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
| | - Wan Xia
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
| | - Rui Zhang
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
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Liu M, Jiang L, Fu X, Wang W, Ma J, Tian T, Nan K, Liang X. Cytoplasmic liver kinase B1 promotes the growth of human lung adenocarcinoma by enhancing autophagy. Cancer Sci 2018; 109:3055-3067. [PMID: 30033530 PMCID: PMC6172065 DOI: 10.1111/cas.13746] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 07/14/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open
Abstract
Liver kinase B1 (LKB1) as a tumor suppression gene that is associated with various kinds of cancers, including lung cancer. In this study, we found that the effect of LKB1 on tumor growth was dependent on its subcellular expression in A549 and HCC827 cells. Full‐length LKB1 decreased the proliferation and clonogenicity of A549‐LKB1 and HCC827‐LKB1 cells, but increased their apoptosis. Opposite effects were observed in A549‐LKB1s and HCC827‐LKB1S cells that overexpressed truncated LKB1 without the nuclear localization sequence. The truncated cytoplasmic LKB1 enhanced the growth of implanted tumors in vivo. The truncated cytoplasmic LKB1 promoted autophagy, which was independent of AMP‐activated protein kinase and mTOR signaling in A549 and HCC827 cells. Further characterization indicated that higher levels of cytoplasmic LKB1 expression were associated with advanced TNM stage and reduced overall survival (OS) in 190 patients with adenocarcinoma. In contrast, high nuclear expression of LKB1 is associated with early TNM stage and longer OS. The high level of cytoplasmic LKB1 expression was an independent risk factor for poor overall survival in patients with adenocarcinoma. Together, our results revealed that cytoplasmic LKB1 promotes the growth of lung adenocarcinoma and could be a prognostic marker for lung adenocarcinoma.
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Affiliation(s)
- Mengjie Liu
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lili Jiang
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao Fu
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjuan Wang
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiequn Ma
- 1st Department of Medical Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Tao Tian
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kejun Nan
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuan Liang
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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