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Luo C, Fang C, Zou R, Jiang J, Zhang M, Ge T, Zhou H, Fan X, Zheng B, Zeng Z. Hyperglycemia-induced DNA damage response activates DNA-PK complex to promote endothelial ferroptosis in type 2 diabetic cardiomyopathy. Theranostics 2025; 15:4507-4525. [PMID: 40225587 PMCID: PMC11984385 DOI: 10.7150/thno.109514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/06/2025] [Indexed: 04/15/2025] Open
Abstract
Rationale: Hyperglycemia-induced endothelial dysfunction is a hallmark of diabetic cardiomyopathy, yet the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate how the DNA damage response (DDR) pathway regulates endothelial cell ferroptosis under hyperglycemic conditions, potentially revealing new therapeutic targets for mitigating cardiac damage in type 2 diabetes mellitus (T2DM). Methods: We performed an integrated analysis of publicly available RNA sequencing datasets (GSE280770, GSE89475, GSE161931, CRA007245) to evaluate the role of DDR in hyperglycemia-induced endothelial dysfunction in vitro and in vivo, including in a T2DM mouse model. Key DDR and ferroptosis markers were validated in cardiac microvascular endothelial cells (CMECs) isolated from mice with streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM, with and without treatment with the DNA-PK inhibitors NU7441 or M9831. Results: Hyperglycemia induced a robust DDR in endothelial cells, characterized by the upregulation of DNA-PK complex genes (PRKDC, XRCC5, XRCC6) and increased markers of DNA damage (γH2AX, 8-oxo-dG). This was accompanied by increased expression of pro-ferroptotic genes (Tfrc, Acsl4, Ptgs2), decreased expression of anti-ferroptotic genes (Gpx4, Slc7a11), and elevated lipid peroxidation (MDA, 4-HNE). Pharmacological inhibition of DNA-PK mitigated these effects, reducing oxidative stress, lipid peroxidation, and endothelial permeability, while improving cardiac contractile and relaxation parameters. Conclusions: Our findings implicate the DNA-PK complex as a key regulator of hyperglycemia-induced endothelial ferroptosis in T2DM cardiomyopathy. Targeting DNA-PK complex may represent a novel therapeutic strategy for mitigating microvascular dysfunction and cardiac decline in T2DM.
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Affiliation(s)
- Cheng Luo
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Chen Fang
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Rongjun Zou
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, Guangdong, China
| | - Jingwei Jiang
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- The First Clinical Medical College of Guangxi Medical University, Nanning, 530021, China
| | - Miao Zhang
- College of Pharmacy, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Teng Ge
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China
| | - Hao Zhou
- University of Rochester Medical Center Rochester, NY, 601 Elmwood Ave, Rochester, NY 14642, United States
| | - Xiaoping Fan
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, Guangdong, China
| | - Baoshi Zheng
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Zhiyu Zeng
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 530021 Nanning, Guangxi, China
- Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, 530021 Nanning, Guangxi, China
- Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, 530021 Nanning, Guangxi, China
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Singh A, Shadangi S, Gupta PK, Rana S. Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies. Compr Physiol 2025; 15:e70003. [PMID: 39980164 DOI: 10.1002/cph4.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/03/2025] [Accepted: 02/07/2025] [Indexed: 02/22/2025]
Abstract
Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.
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Affiliation(s)
- Aditi Singh
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| | - Sucharita Shadangi
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| | - Pulkit Kr Gupta
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| | - Soumendra Rana
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
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Jaiswal A, Yadav P, Rawat PS, Kaur M, Babu SS, Khurana A, Bhatti JS, Navik U. Empagliflozin in diabetic cardiomyopathy: elucidating mechanisms, therapeutic potentials, and future directions. Mol Biol Rep 2025; 52:158. [PMID: 39853512 DOI: 10.1007/s11033-025-10260-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/13/2025] [Indexed: 01/26/2025]
Abstract
Diabetic cardiomyopathy (DCM) represents a significant health burden, exacerbated by the global increase in type 2 diabetes mellitus (T2DM). This condition contributes substantially to the morbidity and mortality associated with diabetes, primarily through myocardial dysfunction independent of coronary artery disease. Current treatment strategies focus on managing symptoms rather than targeting the underlying pathophysiological mechanisms, highlighting a critical need for specific therapeutic interventions. This review explores the multifaceted role of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in addressing the complex etiology of DCM. We discuss the key mechanisms by which hyperglycemia contributes to cardiac dysfunction, including oxidative stress, mitochondrial impairment, and inflammation, and how empagliflozin mitigates these effects. Empagliflozin's effects on reducing hospitalization for heart failure and potentially lowering cardiovascular mortality mark it as a promising candidate for DCM management. By elucidating the underlying mechanisms through which empagliflozin operates, this review underscores its therapeutic potential and paves the way for future research into its broader applications in diabetic cardiac care. This synthesis aims to foster a deeper understanding of DCM and encourage the integration of empagliflozin into treatment paradigms, offering hope for improved outcomes in patients suffering from this debilitating condition.
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Affiliation(s)
- Aiswarya Jaiswal
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Pushkar Singh Rawat
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Maninder Kaur
- Department of Human Anatomy, Bhojia Dental College and Hospital, Budh, Baddi, Himachal Pradesh, 173205, India
| | | | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India.
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4
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Zotova IV, Cherkasov AO. [The Influence of Antithrombotic Therapy on the Risk Factors for Cardiovascular Complications in Patients With Coronary Artery Disease And Diabetes Mellitus. Emphasis on Hypercoagulation]. KARDIOLOGIIA 2024; 64:86-95. [PMID: 39784137 DOI: 10.18087/cardio.2024.12.n2843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 11/29/2024] [Indexed: 01/12/2025]
Abstract
Comorbid diabetes mellitus (DM) in patients with ischemic heart disease (IHD) is a serious factor that significantly impairs the life prognosis and increases the risk of cardiovascular complications (CVC) as well as the likelihood of death. The residual risk of developing CVC in such patients is largely determined by the high thrombotic status, that is associated with hypercoagulation characteristic of DM. Hypercoagulation causes activation of both platelet and coagulation pathways, which leads to an increased susceptibility to thrombosis. In this context, the combined administration of the anticoagulant rivaroxaban (Xarelto®) 2.5 mg and acetylsalicylic acid (ASA) can significantly reduce this risk by affecting both mechanisms of thrombus formation and thereby improving the prognosis. Rivaroxaban 2.5 mg in combination with ASA is the only available strategy to intensify the antithrombotic therapy in patients with stable IHD and DM with no history of ischemic events. Importantly, such therapy should be initiated as early as possible to prevent clinically significant CVCs and improve patients' quality of life.
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Affiliation(s)
- I V Zotova
- Central State Medical Academy of the Administrative Department of the President of the Russian Federation, Moscow
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Rojas-Solé C, Pinilla-González V, Lillo-Moya J, González-Fernández T, Saso L, Rodrigo R. Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy. Redox Rep 2024; 29:2289740. [PMID: 38108325 PMCID: PMC10732214 DOI: 10.1080/13510002.2023.2289740] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023] Open
Abstract
Increased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.
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Affiliation(s)
- Catalina Rojas-Solé
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Víctor Pinilla-González
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - José Lillo-Moya
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Tommy González-Fernández
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Faculty of Pharmacy and Medicine, Sapienza University, Rome, Italy
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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Hasani M, Abbasi-Oshaghi E, Khomari F, Kiani B, Mirzaei F, Alipourfard I, Khodadadi I, Tayebinia H, Babaei M, Alizadeh-Fanalou S, Bahreini E. Enhanced Insulin Secretion Through Upregulation of Transcription Factors by Hydroalcoholic Extract of Securigera securidaca Seeds in Diabetic Animal Model. Endocrinol Diabetes Metab 2024; 7:e515. [PMID: 39238175 PMCID: PMC11377490 DOI: 10.1002/edm2.515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/19/2024] [Accepted: 07/28/2024] [Indexed: 09/07/2024] Open
Abstract
AIM In previous studies, the researchers observed an increase in insulin secretion in STZ-treated diabetic rats following treatment with the hydroalcoholic extract of Securigera securidaca (HESS) seeds. This study focuses on the relationship between the antioxidant properties of HESS with changes in diabetic pancreatic tissue and the gene expression of factors that impact insulin secretion. METHODS In this controlled experimental study, three varying doses of HESS were administered to three groups of diabetic rats induced by STZ. Oxidative stress indicators like total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde were assessed in both pancreatic and liver tissues. Pancreatic histology was studied post-haematoxylin staining. Insulin and FGF21 levels in the blood were measured using the ELISA method. The expression of Nrf2 and FGF21 genes in the pancreas and liver, along with MafA and PDX-1 genes in the pancreas, was quantified using real-time PCR. RESULTS The administration of HESS in varying doses led to a dose-dependent rise in blood insulin levels and a decrease in blood glucose levels and oxidative stress. By reducing oxidative stress, HESS treatment lowered the heightened levels of NRF2 and FGF21 in the liver and pancreas of diabetic rats, improving pancreatic tissue health. As oxidative stress decreased, the expression of MafA and PDX1 genes in the pancreas approached levels seen in healthy rats. CONCLUSION HESS elicits an increase in insulin secretion through the mitigation of oxidative stress and tissue damage, as well as the modulation of gene expression related to the insulin transcription factors PDX-1 and MafA.
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Affiliation(s)
- Maryam Hasani
- Department of Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ebrahim Abbasi-Oshaghi
- Department of Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Khomari
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahar Kiani
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mirzaei
- Department of Anatomical Sciences, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | | | - Iraj Khodadadi
- Department of Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heydar Tayebinia
- Department of Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Babaei
- Department of Clinical Sciences, Faculty of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Shahin Alizadeh-Fanalou
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Elham Bahreini
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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7
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Attia SM, Albekairi NA, Alshamrani AA, Ahmad SF, Almutairi F, Attia MSM, Ansari MA, Bakheet SA, Harisa GI, Nadeem A. Dapagliflozin suppresses diabetes-induced oxidative DNA damage and hypermethylation in mouse somatic cells. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2024; 896:503765. [PMID: 38821673 DOI: 10.1016/j.mrgentox.2024.503765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 06/02/2024]
Abstract
Diabetes mellitus is a complex metabolic disorder resulting from the interplay of environmental, genetic, and epigenetic factors that increase the risk of cancer development. However, it is unclear whether the increased cancer risk is due to poor glycemic control or the use of some antidiabetic medications. Therefore, we investigated the genetic and epigenetic changes in somatic cells in a mouse model of diabetes and studied whether multiple exposures to the antidiabetic medication dapagliflozin influence these changes. We also elucidated the mechanism(s) of these ameliorations. The micronucleus test and modified comet assay were used to investigate bone marrow DNA damage and methylation changes. These assays revealed that dapagliflozin is non-genotoxic in the tested regimen, and oxidative DNA damage and hypermethylation were significantly higher in diabetic mice. Spectrophotometry also evaluated oxidative DNA damage and global DNA methylation, revealing similar significant alterations induced by diabetes. Conversely, the dapagliflozin-treated diabetic animals significantly reduced these changes. The expression of some genes involved in DNA repair and DNA methylation was disrupted considerably in the somatic cells of diabetic animals. In contrast, dapagliflozin treatment significantly restored these disruptions and enhanced DNA repair. The simultaneous effects of decreased oxidative DNA damage and hypermethylation levels suggest that dapagliflozin can be used as a safe antidiabetic drug to reduce DNA damage and hypermethylation in diabetes, demonstrating its usefulness in patients with diabetes to control hyperglycemia and decrease the development of its subsequent complications.
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Affiliation(s)
- Sabry M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
| | - Norah A Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ali A Alshamrani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sheikh F Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Faris Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohamed S M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mushtaq A Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Gamaleldin I Harisa
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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8
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Zhang C, Gu L, Xie H, Liu Y, Huang P, Zhang J, Luo D, Zhang J. Glucose transport, transporters and metabolism in diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166995. [PMID: 38142757 DOI: 10.1016/j.bbadis.2023.166995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 12/02/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023]
Abstract
Diabetic retinopathy (DR) is the most common reason for blindness in working-age individuals globally. Prolonged high blood glucose is a main causative factor for DR development, and glucose transport is prerequisite for the disturbances in DR caused by hyperglycemia. Glucose transport is mediated by its transporters, including the facilitated transporters (glucose transporter, GLUTs), the "active" glucose transporters (sodium-dependent glucose transporters, SGLTs), and the SLC50 family of uniporters (sugars will eventually be exported transporters, SWEETs). Glucose transport across the blood-retinal barrier (BRB) is crucial for nourishing the neuronal retina in the context of retinal physiology. This physiological process primarily relies on GLUTs and SGLTs, which mediate the glucose transportation across both the cell membrane of retinal capillary endothelial cells and the retinal pigment epithelium (RPE). Under diabetic conditions, increased accumulation of extracellular glucose enhances the retinal cellular glucose uptake and metabolism via both glycolysis and glycolytic side branches, which activates several biochemical pathways, including the protein kinase C (PKC), advanced glycation end-products (AGEs), polyol pathway and hexosamine biosynthetic pathway (HBP). These activated biochemical pathways further increase the production of reactive oxygen species (ROS), leading to oxidative stress and activation of Poly (ADP-ribose) polymerase (PARP). The activated PARP further affects all the cellular components in the retina, and finally resulting in microangiopathy, neurodegeneration and low-to-moderate grade inflammation in DR. This review aims to discuss the changes of glucose transport, glucose transporters, as well as its metabolism in DR, which influences the retinal neurovascular unit (NVU) and implies the possible therapeutic strategies for treating DR.
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Affiliation(s)
- Chaoyang Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
| | - Limin Gu
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, China.
| | - Hai Xie
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
| | - Yan Liu
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
| | - Peirong Huang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
| | - Jingting Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
| | - Dawei Luo
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
| | - Jingfa Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases; Shanghai Clinical Research Center for Eye Diseases; Shanghai Key Clinical Specialty; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Research Institute, Shanghai, China.
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9
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Hai Y, Ren K, Zhang Y, Yang L, Cao H, Yuan X, Su L, Li H, Feng X, Liu D. HIF-1α serves as a co-linker between AD and T2DM. Biomed Pharmacother 2024; 171:116158. [PMID: 38242039 DOI: 10.1016/j.biopha.2024.116158] [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: 09/24/2023] [Revised: 12/27/2023] [Accepted: 01/11/2024] [Indexed: 01/21/2024] Open
Abstract
Alzheimer's disease (AD)-related brain deterioration is linked to the type 2 diabetes mellitus (T2DM) features hyperglycemia, hyperinsulinemia, and insulin resistance. Hypoxia as a common risk factor for both AD and T2DM. Hypoxia-inducible factor-1 alpha (HIF-1α) acts as the main regulator of the hypoxia response and may be a key target in the comorbidity of AD and T2DM. HIF-1α expression is closely related to hyperglycemia, insulin resistance, and inflammation. Tissue oxygen consumption disrupts HIF-1α homeostasis, leading to increased reactive oxygen species levels and the inhibition of insulin receptor pathway activity, causing neuroinflammation, insulin resistance, abnormal Aβ deposition, and tau hyperphosphorylation. HIF-1α activation also leads to the deposition of Aβ by promoting the abnormal shearing of amyloid precursor protein and inhibiting the degradation of Aβ, and it promotes tau hyperphosphorylation by activating oxidative stress and the activation of astrocytes, which further exasperates AD. Therefore, we believe that HIF-α has great potential as a target for the treatment of AD. Importantly, the intracellular homeostasis of HIF-1α is a more crucial factor than its expression level.
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Affiliation(s)
- Yang Hai
- Scientific Research and Experimental Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China; Key Laboratory of Dunhuang Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China.
| | - Ke Ren
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Yarong Zhang
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Lili Yang
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Haoshi Cao
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Xianxia Yuan
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Linling Su
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Hailong Li
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Xiaoli Feng
- Scientific Research and Experimental Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China; Key Laboratory of Dunhuang Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China
| | - Dongling Liu
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, PR China; Northwest Collaborative Innovation Center for Traditional Chinese Medicine, Lanzhou 730000, Gansu Province, PR China; Gansu Pharmaceutical Industry Innovation Research Institute, Lanzhou 730000, Gansu Province, PR China.
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10
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Zhu J, Hu Z, Luo Y, Liu Y, Luo W, Du X, Luo Z, Hu J, Peng S. Diabetic peripheral neuropathy: pathogenetic mechanisms and treatment. Front Endocrinol (Lausanne) 2024; 14:1265372. [PMID: 38264279 PMCID: PMC10803883 DOI: 10.3389/fendo.2023.1265372] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 12/14/2023] [Indexed: 01/25/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) refers to the development of peripheral nerve dysfunction in patients with diabetes when other causes are excluded. Diabetic distal symmetric polyneuropathy (DSPN) is the most representative form of DPN. As one of the most common complications of diabetes, its prevalence increases with the duration of diabetes. 10-15% of newly diagnosed T2DM patients have DSPN, and the prevalence can exceed 50% in patients with diabetes for more than 10 years. Bilateral limb pain, numbness, and paresthesia are the most common clinical manifestations in patients with DPN, and in severe cases, foot ulcers can occur, even leading to amputation. The etiology and pathogenesis of diabetic neuropathy are not yet completely clarified, but hyperglycemia, disorders of lipid metabolism, and abnormalities in insulin signaling pathways are currently considered to be the initiating factors for a range of pathophysiological changes in DPN. In the presence of abnormal metabolic factors, the normal structure and function of the entire peripheral nervous system are disrupted, including myelinated and unmyelinated nerve axons, perikaryon, neurovascular, and glial cells. In addition, abnormalities in the insulin signaling pathway will inhibit neural axon repair and promote apoptosis of damaged cells. Here, we will discuss recent advances in the study of DPN mechanisms, including oxidative stress pathways, mechanisms of microvascular damage, mechanisms of damage to insulin receptor signaling pathways, and other potential mechanisms associated with neuroinflammation, mitochondrial dysfunction, and cellular oxidative damage. Identifying the contributions from each pathway to neuropathy and the associations between them may help us to further explore more targeted screening and treatment interventions.
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Affiliation(s)
- Jinxi Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ziyan Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yifan Luo
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yinuo Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaohong Du
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhenzhong Luo
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jialing Hu
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shengliang Peng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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11
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Saleh DO, Sedik AA. Novel drugs affecting diabetic peripheral neuropathy. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:657-670. [PMID: 38645500 PMCID: PMC11024403 DOI: 10.22038/ijbms.2024.75367.16334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/27/2023] [Indexed: 04/23/2024]
Abstract
Diabetic peripheral neuropathy (DPN) poses a significant threat, affecting half of the global diabetic population and leading to severe complications, including pain, impaired mobility, and potential amputation. The delayed manifestation of diabetic neuropathy (DN) makes early diagnosis challenging, contributing to its debilitating impact on individuals with diabetes mellitus (DM). This review examines the multifaceted nature of DPN, focusing on the intricate interplay between oxidative stress, metabolic pathways, and the resulting neuronal damage. It delves into the challenges of diagnosing DN, emphasizing the critical role played by hyperglycemia in triggering these cascading effects. Furthermore, the study explores the limitations of current neuropathic pain drugs, prompting an investigation into a myriad of pharmaceutical agents tested in both human and animal trials over the past decade. The methodology scrutinizes these agents for their potential to provide symptomatic relief for DPN. The investigation reveals promising results from various pharmaceutical agents tested for DPN relief, showcasing their efficacy in ameliorating symptoms. However, a notable gap persists in addressing the underlying problem of DPN. The results underscore the complexity of DPN and the challenges in developing therapies that go beyond symptomatic relief. Despite advancements in treating DPN symptoms, there remains a scarcity of options addressing the underlying problem. This review consolidates the state-of-the-art drugs designed to combat DPN, highlighting their efficacy in alleviating symptoms. Additionally, it emphasizes the need for a deeper understanding of the diverse processes and pathways involved in DPN pathogenesis.
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Affiliation(s)
- Dalia O. Saleh
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, 12622, Egypt
| | - Ahmed A. Sedik
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, 12622, Egypt
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12
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Dwivedi J, Wal P, Dash B, Ovais M, Sachan P, Verma V. Diabetic Pneumopathy- A Novel Diabetes-associated Complication: Pathophysiology, the Underlying Mechanism and Combination Medication. Endocr Metab Immune Disord Drug Targets 2024; 24:1027-1052. [PMID: 37817659 DOI: 10.2174/0118715303265960230926113201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/03/2023] [Accepted: 07/20/2023] [Indexed: 10/12/2023]
Abstract
BACKGROUND The "diabetic lung" has been identified as a possible target organ in diabetes, with abnormalities in ventilation control, bronchomotor tone, lung volume, pulmonary diffusing capacity, and neuroadrenergic bronchial innervation. OBJECTIVE This review summarizes studies related to diabetic pneumopathy, pathophysiology and a number of pulmonary disorders including type 1 and type 2 diabetes. METHODS Electronic searches were conducted on databases such as Pub Med, Wiley Online Library (WOL), Scopus, Elsevier, ScienceDirect, and Google Scholar using standard keywords "diabetes," "diabetes Pneumopathy," "Pathophysiology," "Lung diseases," "lung infection" for review articles published between 1978 to 2023 very few previous review articles based their focus on diabetic pneumopathy and its pathophysiology. RESULTS Globally, the incidence of diabetes mellitus has been rising. It is a chronic, progressive metabolic disease. The "diabetic lung" may serve as a model of accelerated ageing since diabetics' rate of respiratory function deterioration is two to three-times higher than that of normal, non-smoking people. CONCLUSION Diabetes-induced pulmonary dysfunction has not gained the attention it deserves due to a lack of proven causality and changes in cellular properties. The mechanism underlying a particular lung illness can still only be partially activated by diabetes but there is evidence that hyperglycemia is linked to pulmonary fibrosis in diabetic people.
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Affiliation(s)
- Jyotsana Dwivedi
- PSIT- Pranveer Singh Institute of Technology (Pharmacy), Kanpur, India
| | - Pranay Wal
- PSIT- Pranveer Singh Institute of Technology (Pharmacy), Kanpur, India
| | - Biswajit Dash
- Department of Pharmaceutical Technology, ADAMAS University, West Bengal, India
| | | | - Pranjal Sachan
- PSIT- Pranveer Singh Institute of Technology (Pharmacy), Kanpur, India
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13
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Liu QJ, Yuan W, Yang P, Shao C. Role of glycolysis in diabetic atherosclerosis. World J Diabetes 2023; 14:1478-1492. [PMID: 37970130 PMCID: PMC10642412 DOI: 10.4239/wjd.v14.i10.1478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/16/2023] [Accepted: 09/14/2023] [Indexed: 10/09/2023] Open
Abstract
Diabetes mellitus is a kind of typical metabolic disorder characterized by elevated blood sugar levels. Atherosclerosis (AS) is one of the most common complications of diabetes. Modern lifestyles and trends that promote overconsumption and unhealthy practices have contributed to an increase in the annual incidence of diabetic AS worldwide, which has created a heavy burden on society. Several studies have shown the significant effects of glycolysis-related changes on the occurrence and development of diabetic AS, which may serve as novel thera-peutic targets for diabetic AS in the future. Glycolysis is an important metabolic pathway that generates energy in various cells of the blood vessel wall. In particular, it plays a vital role in the physiological and pathological activities of the three important cells, Endothelial cells, macrophages and vascular smooth muscle cells. There are lots of similar mechanisms underlying diabetic and common AS, the former is more complex. In this article, we describe the role and mechanism underlying glycolysis in diabetic AS, as well as the therapeutic targets, such as trained immunity, microRNAs, gut microbiota, and associated drugs, with the aim to provide some new perspectives and potentially feasible programs for the treatment of diabetic AS in the foreseeable future.
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Affiliation(s)
- Qian-Jia Liu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Ping Yang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
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14
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Torres-Méndez JK, Niño-Narvión J, Martinez-Santos P, Diarte-Añazco EMG, Méndez-Lara KA, Del Olmo TV, Rotllan N, Julián MT, Alonso N, Mauricio D, Camacho M, Muñoz JP, Rossell J, Julve J. Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms. Nutrients 2023; 15:3083. [PMID: 37513501 PMCID: PMC10383777 DOI: 10.3390/nu15143083] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/02/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNFα: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFκB (p65) signaling in treated diabetic mice (NFκB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFκB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling.
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Affiliation(s)
| | - Julia Niño-Narvión
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- Departamento de Bioquímica y Biología Molecular B e Inmunología, Facultad de Medicina, Universidad de Murcia (UMU), 30120 Murcia, Spain
| | | | | | | | | | - Noemi Rotllan
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria Teresa Julián
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
| | - Núria Alonso
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
| | - Didac Mauricio
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
- Faculty of Medicine, University of Vic/Central University of Catalonia (UVIC/UCC), 08500 Vic, Spain
| | - Mercedes Camacho
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Juan Pablo Muñoz
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Joana Rossell
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
| | - Josep Julve
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
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15
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Balkrishna A, Pathak R, Bhatt S, Arya V. Molecular Insights of Plant Phytochemicals Against Diabetic Neuropathy. Curr Diabetes Rev 2023; 19:e250822207994. [PMID: 36028963 DOI: 10.2174/1573399819666220825124510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/23/2022] [Accepted: 04/26/2022] [Indexed: 11/22/2022]
Abstract
Diabetes and its associated complications including diabetic neuropathy have become a menacing headache for health workers and scientists all over the world. The number of diabetic individuals has been growing exponentially every day while the entire medical fraternity feels crippled and unable to handle such an enormous and anarchical scenario. The disease also demonstrates itself in the patients in numerous ways ranging from a little discomfort to death. Diabetic neuropathy has a poor prognosis since it might go unnoticed for years after the onset of diabetes. The etiology of the disease has been linked to oxidative stress caused by increased free radical production. Hyperglycemia causes multiple metabolic pathways to be activated, as well as significant oxidative stress, which becomes the major cause of cell death, culminating in Diabetic Neuropathy. So, it is the need of the hour to find out permanent treatment for this life-threatening disease. The primary goal of this study is to emphasize the potential importance of numerous processes and pathways in the development of diabetic neuropathy as well as the possible role of plant metabolites to control the disease at a molecular level. A possible mechanism was also summarized in the study about scavenging the reactive oxygen species by a flavonoid component. The study also covered the in vivo data of various plants and some of the flavonoid compounds actively studied against Diabetic Neuropathy by inhibiting or reducing the contributing factors such as proinflammatory cytokines, ROS, RNS inhibition, and upregulating the various cellular antioxidants such as GSH, SOD, and CAT.
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Affiliation(s)
- Acharya Balkrishna
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
| | - Rakshit Pathak
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
| | - Shalini Bhatt
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
| | - Vedpriya Arya
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
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16
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Qureshi Z, Ali MN, Khalid M. An Insight into Potential Pharmacotherapeutic Agents for Painful Diabetic Neuropathy. J Diabetes Res 2022; 2022:9989272. [PMID: 35127954 PMCID: PMC8813291 DOI: 10.1155/2022/9989272] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 11/11/2021] [Accepted: 12/27/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetes is the 4th most common disease affecting the world's population. It is accompanied by many complications that deteriorate the quality of life. Painful diabetic neuropathy (PDN) is one of the debilitating consequences of diabetes that effects one-third of diabetic patients. Unfortunately, there is no internationally recommended drug that directly hinders the pathological mechanisms that result in painful diabetic neuropathy. Clinical studies have shown that anticonvulsant and antidepressant therapies have proven fruitful in management of pain associated with PDN. Currently, the FDA approved medications for painful diabetic neuropathies include duloxetine, pregabalin, tapentadol extended release, and capsaicin (for foot PDN only). The FDA has also approved the use of spinal cord stimulation system for the treatment of diabetic neuropathy pain. The drugs recommended by other regulatory bodies include gabapentin, amitriptyline, dextromethorphan, tramadol, venlafaxine, sodium valproate, and 5 % lidocaine patch. These drugs are only partially effective and have adverse effects associated with their use. Treating painful symptoms in diabetic patient can be frustrating not only for the patients but also for health care workers, so additional clinical trials for novel and conventional treatments are required to devise more effective treatment for PDN with minimal side effects. This review gives an insight on the pathways involved in the pathogenesis of PDN and the potential pharmacotherapeutic agents. This will be followed by an overview on the FDA-approved drugs for PDN and commercially available topical analgesic and their effects on painful diabetic neuropathies.
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Affiliation(s)
- Zunaira Qureshi
- Department of Biomedical Engineering and Sciences, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, H-12, 44000 Islamabad, Pakistan
| | - Murtaza Najabat Ali
- Department of Biomedical Engineering and Sciences, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, H-12, 44000 Islamabad, Pakistan
| | - Minahil Khalid
- Department of Biomedical Engineering and Sciences, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, H-12, 44000 Islamabad, Pakistan
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17
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Dang Y, Lai Y, Chen F, Sun Q, Ding C, Zhang W, Xu Z. Activatable NIR-II Fluorescent Nanoprobe for Rapid Detection and Imaging of Methylglyoxal Facilitated by the Local Nonpolar Microenvironment. Anal Chem 2022; 94:1076-1084. [DOI: 10.1021/acs.analchem.1c04076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Yijing Dang
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Yi Lai
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Fengping Chen
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Qian Sun
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Chunyong Ding
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Wen Zhang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China
| | - Zhiai Xu
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
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18
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Shivashankar G, Lim JC, Acosta ML. Glyceraldehyde-3-phosphate dehydrogenase and glutamine synthetase inhibition in the presence of pro-inflammatory cytokines contribute to the metabolic imbalance of diabetic retinopathy. Exp Eye Res 2021; 213:108845. [PMID: 34800480 DOI: 10.1016/j.exer.2021.108845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/12/2021] [Accepted: 11/12/2021] [Indexed: 12/18/2022]
Abstract
Diabetic retinopathy (DR) is the leading cause of vision impairment in working age adults. In addition to hyperglycemia, retinal inflammation is an important driving factor for DR development. Although DR is clinically described as diabetes-induced damage to the retinal blood vessels, several studies have reported that metabolic dysregulation occurs in the retina prior to the development of microvascular damage. The two most commonly affected metabolic pathways in diabetic conditions are glycolysis and the glutamate pathway. We investigated the role of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and glutamine synthetase (GS) in an in-vitro model of DR incorporating high glucose and pro-inflammatory cytokines. We found that GAPDH and GS enzyme activity were not significantly affected in hyperglycemic conditions or after exposure to cytokines alone, but were significantly decreased in the DR model. This confirmed that pro-inflammatory cytokines IL-1β and TNFα enhance the hyperglycemic metabolic deficit. We further investigated metabolite and amino acid levels after specific pharmacological inhibition of GAPDH or GS in the absence/presence of pro-inflammatory cytokines. The results indicate that GAPDH inhibition increased glucose and addition of cytokines increased lactate and ATP levels and reduced glutamate levels. GS inhibition did not alter retinal metabolite levels but the addition of cytokines increased ATP levels and caused glutamate accumulation in Müller cells. We conclude that it is the action of pro-inflammatory cytokines concomitantly with the inhibition of the glycolytic or GS mediated glutamate recycling that contribute to metabolic dysregulation in DR. Therefore, in the absence of good glycemic control, therapeutic interventions aimed at regulating inflammation may prevent the onset of early metabolic imbalance in DR.
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Affiliation(s)
- Gaganashree Shivashankar
- School of Optometry and Vision Science and the New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
| | - Julie C Lim
- Department of Physiology, School of Medical and Health Sciences and the New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
| | - Monica L Acosta
- School of Optometry and Vision Science and the New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
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19
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Maluchenko NV, Feofanov AV, Studitsky VM. PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols. Int J Mol Sci 2021; 22:11441. [PMID: 34768872 PMCID: PMC8584120 DOI: 10.3390/ijms222111441] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 02/06/2023] Open
Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.
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Affiliation(s)
- Natalya V. Maluchenko
- Biology Faculty, Lomonosov Moscow State University, Lenin Hills 1/12, 119234 Moscow, Russia; (A.V.F.); (V.M.S.)
| | - Alexey V. Feofanov
- Biology Faculty, Lomonosov Moscow State University, Lenin Hills 1/12, 119234 Moscow, Russia; (A.V.F.); (V.M.S.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Mikluko-Maklaya Str., 16/10, 117997 Moscow, Russia
| | - Vasily M. Studitsky
- Biology Faculty, Lomonosov Moscow State University, Lenin Hills 1/12, 119234 Moscow, Russia; (A.V.F.); (V.M.S.)
- Fox Chase Cancer Center, Cottman Avenue 333, Philadelphia, PA 19111, USA
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20
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Li Z, Shen H, Liu Y, Zhou X, Yan M, He H, Zhao T, Zhang H, Li P. Subproteomic profiling from renal cortices in OLETF rats reveals mutations of multiple novel genes in diabetic nephropathy. Genes Genomics 2021; 44:109-122. [PMID: 34643893 DOI: 10.1007/s13258-021-01174-0] [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: 07/19/2020] [Accepted: 09/29/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a serious threat to human health, but its pathogenesis is not fully understood. Otsuka Long-Evans Tokushima Fatty (OLETF) rats are very similar to human DN in many aspects such as pathological changes and processes, and are deemed to be an ideal rodent model. OBJECTIVE This study was aimed to explore the pathogenesis of DN by analyzing the protein expression profile from renal cortices in OLETF rats. METHODS Thirty-six-week-old diabetic OLETF rats and normal control Long-Evans Tokushima Otsuka (LETO) rats were nephrectomized, and the renal cortices were isolated. The proteins were separated by soluble and insoluble high-resolution subproteomics methods for the analysis and identification of differential proteins. RESULTS Thirty-six differentially expressed proteins were found. Among them, 11 proteins had different isoelectric points and molecular weights between OLETF and LETO rats. Further sequencing identified point mutations in genes encoding eight of these proteins, which are involved in many biological processes closely related to DN, including oxidative stress and inflammation. Five of these eight proteins have not been reported in DN. CONCLUSION This study reveals mutations of multiple novel genes in diabetic OLETF rats, providing some new potential targets for the pathogenesis of DN and helping to better understand the pathogenesis of DN.
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Affiliation(s)
- Zhiguo Li
- Department of School of Public Health, International Science and Technology Cooperation Base of Geriatric Medicine, The Hebei Key Lab for Organ Fibrosis, The Hebei Key Lab for chronic disease, North China University of Science and Technology, Tangshan, 063000, China
| | - Hong Shen
- Department of Modern Technology and Education, North China University of Science and Technology, Tangshan, 063000, China
| | - Yeqiang Liu
- Department of Endocrinology, Kailuan General Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Xuefeng Zhou
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Science, China-Japan Friendship Hospital, 2 Yinghua East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Meihua Yan
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Science, China-Japan Friendship Hospital, 2 Yinghua East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Hailan He
- School of Graduate Studies, North China University of Science and Technology, Tangshan, 063000, China
| | - Tingting Zhao
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Science, China-Japan Friendship Hospital, 2 Yinghua East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Haojun Zhang
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Science, China-Japan Friendship Hospital, 2 Yinghua East Road, Chaoyang District, Beijing, 100029, People's Republic of China.
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Science, China-Japan Friendship Hospital, 2 Yinghua East Road, Chaoyang District, Beijing, 100029, People's Republic of China.
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21
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Yako H, Niimi N, Kato A, Takaku S, Tatsumi Y, Nishito Y, Kato K, Sango K. Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions. Sci Rep 2021; 11:18910. [PMID: 34556698 PMCID: PMC8460646 DOI: 10.1038/s41598-021-98082-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/03/2021] [Indexed: 11/25/2022] Open
Abstract
Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis–TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.
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Affiliation(s)
- Hideji Yako
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
| | - Naoko Niimi
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan
| | - Ayako Kato
- Laboratory of Medicine, Aichi Gakuin University, School of Pharmacy, Nagoya, Japan
| | - Shizuka Takaku
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan
| | - Yasuaki Tatsumi
- Laboratory of Medicine, Aichi Gakuin University, School of Pharmacy, Nagoya, Japan
| | - Yasumasa Nishito
- Basic Technology Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Koichi Kato
- Laboratory of Medicine, Aichi Gakuin University, School of Pharmacy, Nagoya, Japan
| | - Kazunori Sango
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
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22
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Wang ZY, Guo MQ, Cui QK, Yuan H, Shan-Ji Fu, Liu B, Xie F, Qiao W, Cheng J, Wang Y, Zhang MX. PARP1 deficiency protects against hyperglycemia-induced neointimal hyperplasia by upregulating TFPI2 activity in diabetic mice. Redox Biol 2021; 46:102084. [PMID: 34364219 PMCID: PMC8353360 DOI: 10.1016/j.redox.2021.102084] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 12/09/2022] Open
Abstract
Diabetes mellitus (DM) promotes neointimal hyperplasia, characterized by dysregulated proliferation and accumulation of vascular smooth muscle cells (VSMCs), leading to occlusive disorders, such as atherosclerosis and stenosis. Poly (ADP-ribose) polymerase 1 (PARP1), reported as a crucial mediator in tumor proliferation and transformation, has a pivotal role in DM. Nonetheless, the function and potential mechanism of PARP1 in diabetic neointimal hyperplasia remain unclear. In this study, we constructed PARP1 conventional knockout (PARP1−/−) mice, and ligation of the left common carotid artery was performed to induce neointimal hyperplasia in Type I diabetes mellitus (T1DM) mouse models. PARP1 expression in the aorta arteries of T1DM mice increased significantly and genetic deletion of PARP1 showed an inhibitory effect on the neointimal hyperplasia. Furthermore, our results revealed that PARP1 enhanced diabetic neointimal hyperplasia via downregulating tissue factor pathway inhibitor (TFPI2), a suppressor of vascular smooth muscle cell proliferation and migration, in which PARP1 acts as a negative transcription factor augmenting TFPI2 promoter DNA methylation. In conclusion, these results suggested that PARP1 accelerates the process of hyperglycemia-induced neointimal hyperplasia via promoting VSMCs proliferation and migration in a TFPI2 dependent manner.
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Affiliation(s)
- Zhao-Yang Wang
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
| | - Meng-Qi Guo
- Department of Cardiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Qing-Ke Cui
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong, China
| | - Haitao Yuan
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Shan-Ji Fu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Bin Liu
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Fei Xie
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Wen Qiao
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Cheng
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ying Wang
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Ming-Xiang Zhang
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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23
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Felisbino K, Granzotti JG, Bello-Santos L, Guiloski IC. Nutrigenomics in Regulating the Expression of Genes Related to Type 2 Diabetes Mellitus. Front Physiol 2021; 12:699220. [PMID: 34366888 PMCID: PMC8334860 DOI: 10.3389/fphys.2021.699220] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/27/2021] [Indexed: 12/13/2022] Open
Abstract
Nutrigenomics is the study of the gene-nutrient interaction and it indicates that some nutrients, called bioactive compounds, can mold the genetic expression or change the nucleotide chain. Polyphenols are secondary metabolites found in plants that are regularly consumed in functional foods and help prevent or delay the onset of type 2 diabetes mellitus (T2DM) and its complications. This article objected to review studies about the interaction of diet with polyphenols and Mediterranean diet in the expression of human genes related to T2DM. Resveratrol acts as an antioxidant, anti-inflammatory, and increases mitochondrial function. Regular consumption of quercetin resulted in improvement of hypertension and suppression of diabetes-induced vasoconstriction. Genistein also showed positive results in T2DM, such as increased cell mass and improved glucose tolerance and insulin levels. Catechins showed efficiency in inducing genes in triacylglycerol biosynthesis, inhibition of fatty acids and cholesterol, and resulting in their participation in mitigating complications of diabetes. Lastly, curcumin was demonstrated to be a protector of the pancreatic islets against streptozotocin-induced oxidative stress. Growing evidence suggest that bioactive compounds such as polyphenols have an important role in T2DM and the prevention and treatment of its complication, as they cause activation or inhibition of related genes.
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Affiliation(s)
- Karoline Felisbino
- Centro de Ensino Superior de Maringá (CESUMAR), Curitiba, Brazil
- Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, Brazil
- Instituto de Pesquisas Pelé Pequeno Príncipe, Curitiba, Brazil
| | | | | | - Izonete Cristina Guiloski
- Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, Brazil
- Instituto de Pesquisas Pelé Pequeno Príncipe, Curitiba, Brazil
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24
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Oka SI, Byun J, Huang CY, Imai N, Ralda G, Zhai P, Xu X, Kashyap S, Warren JS, Alan Maschek J, Tippetts TS, Tong M, Venkatesh S, Ikeda Y, Mizushima W, Kashihara T, Sadoshima J. Nampt Potentiates Antioxidant Defense in Diabetic Cardiomyopathy. Circ Res 2021; 129:114-130. [PMID: 33928788 PMCID: PMC8513534 DOI: 10.1161/circresaha.120.317943] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
[Figure: see text].
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MESH Headings
- Animals
- Antioxidants/metabolism
- Apoptosis
- Autophagy
- Cells, Cultured
- Cytokines/genetics
- Cytokines/metabolism
- Diabetic Cardiomyopathies/enzymology
- Diabetic Cardiomyopathies/genetics
- Diabetic Cardiomyopathies/pathology
- Diet, High-Fat
- Disease Models, Animal
- Fibrosis
- Glutathione/metabolism
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Heart/enzymology
- Mitochondria, Heart/genetics
- Mitochondria, Heart/pathology
- Mitophagy
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/pathology
- NAD/metabolism
- NADP/metabolism
- Nicotinamide Phosphoribosyltransferase/genetics
- Nicotinamide Phosphoribosyltransferase/metabolism
- Oxidative Stress
- Rats, Wistar
- Sirtuins/genetics
- Sirtuins/metabolism
- Thioredoxins/metabolism
- Mice
- Rats
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Affiliation(s)
- Shin-Ichi Oka
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Jaemin Byun
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Chun-Yang Huang
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
- Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan (C.-y.H.)
- Institute of Clinical Medicine, School of Medicine National Yang-Ming University, Taipei, Taiwan (C.-y.H.)
| | - Nobushige Imai
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Guersom Ralda
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Peiyong Zhai
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Xiaoyong Xu
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Zhejiang, China (X.X.)
| | - Sanchita Kashyap
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Junco S Warren
- Nora Eccles Harrison Cardiovascular Research and Training Institute (J.S.W.), University of Utah, Salt Lake City
| | - John Alan Maschek
- Metabolomics, Proteomics, and Mass Spectrometry Cores (J.A.M.), University of Utah, Salt Lake City
- Department of Nutrition and Integrative Physiology (J.A.M.), University of Utah, Salt Lake City
| | - Trevor S Tippetts
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center (T.S.T., S.V.), University of Utah, Salt Lake City
| | - Mingming Tong
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Sundararajan Venkatesh
- Department of Microbiology, Biochemistry, and Molecular Genetics (S.V.), Rutgers New Jersey Medical School, Newark
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center (T.S.T., S.V.), University of Utah, Salt Lake City
| | - Yoshiyuki Ikeda
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Wataru Mizushima
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Toshihide Kashihara
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine (S.-i.O., J.B., C.-y.H., N.I., G.R., P.Z., X.X., S.K., M.T., Y.I., W.M., T.K., J.S.), Rutgers New Jersey Medical School, Newark
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25
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Pal S, Rao GN, Pal A. Inflammation and apoptosis, two key events induced by hyperglycemia mediated reactive nitrogen species in RGC-5 cells. Life Sci 2021; 279:119693. [PMID: 34111464 DOI: 10.1016/j.lfs.2021.119693] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/23/2021] [Accepted: 05/31/2021] [Indexed: 12/21/2022]
Abstract
Nitrosative stress plays a critical role in retinal injury in high glucose (HG) environment of eye, but the mechanisms remain poorly understood. Here we tested the hypothesis that HG induced reactive nitrogen species (RNS) production acts as a key functional mediator of antioxidant depletion, mitochondrial dysfunction, biomolecule damage, inflammation and apoptosis. Our findings illustrated that exposure of cultured RGC-5 cells to HG significantly disrupts the antioxidant defense mechanism and mitochondrial machineries by increasing the loss of mitochondrial membrane potential (ΔѰM) and elevating mitochondrial mass. Furthermore, we used biochemical tools to analyze the changes in metabolites, sulfur amino acids (SAAs) such as L-glutathione (GSH) and L-cysteine (Cys), in the presence of HG environment. These metabolic changes were followed by an increase in glycolytic flux that is phosphofructokinase-2 (PFK-2) activity. Moreover, HG exposure results in a significant disruption of protein carbonylation (PC) and lipid peroxidation (LPO), downregulation of OGG1 and increase in 8-OHdG accumulations in RGC-5 cells. In addition, our results demonstrated that HG environment coinciding with increased expression of inflammatory mediators, cell cycle deregulation, decreased in cell viability and expression of FoxOs, increased lysosomal content leading to apoptosis. Pre-treatment of selective inhibitors of RNS significantly reduced the HG-induced cell cycle deregulation and apoptosis in RGC-5 cells. Collectively, these results illustrated that accumulated RNS exacerbates the antioxidant depletion, mitochondrial dysfunction, biomolecule damage, inflammation and apoptosis induced by HG exposure in RGC-5 cells. Treatment of pharmacological inhibitors attenuated the HG induced in retinal cells.
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Affiliation(s)
- Sweta Pal
- School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 751024, India
| | - G Nageswar Rao
- Department of Ophthalmology, Kalinga Institute of Medical Sciences, Kalinga Institute of Industrial Technology, Bhubaneswar 751024, India
| | - Arttatrana Pal
- School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 751024, India; Department of Zoology, School of Life Sciences, Mahatma Gandhi Central University, Motihari 845401, India.
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26
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Ugbaja RN, Fatokun TP, Akinloye DI, James AS, Onabanjo OO, Akinloye OA. Propolis ethanol extract abrogates hyperglycemia, lipotoxicity, and lowered hepatic poly (ADP-ribose) polymerase protein level in male albino rats. J Diabetes Metab Disord 2021; 20:683-696. [PMID: 34178859 PMCID: PMC8212341 DOI: 10.1007/s40200-021-00800-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/13/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND AND AIM Diabetes is a major cause of death worldwide and currently available allopathic drugs presents adverse side effects, thus, necessitating a continuous screening for natural products. This study therefore investigated the effects of Propolis Ethanol Extract (PEE) on blood sugar, lipid metabolism, and poly-(ADP)-ribose polymerase (PARPs) protein level of diabetic male Wistar rats. METHODOLOGY Seventy rats weighing between (150-180) g used in this study were randomized into seven (7) groups as follows: group 1 (Normal control given Olive oil), group 2 (Diabetic control given Olive oil), group 3 [Diabetic + PEE (200 mg/kg)], group 4 [Diabetic + (PEE 600 mg/kg)], group 5 [Diabetic + Glibenclamide (10 mg/kg)], group 6 [Normal + PEE (200 mg/kg)], and group 7 [Normal + PEE (600 mg/kg)]. Diabetes was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg in 0.1 M citrate buffer pH 4.5), while the vehicle and PEE were orally administered once daily. Treatment with PEE commenced after the confirmation of diabetes. Five rats from each group were sacrificed after the third and sixth weeks of PEE treatment. RESULTS Administration of PEE significantly (P < 0.05) lowered the elevated fasting blood sugar, improves body weight, and abated lipotoxicity in the brain, heart, liver and kidney of the treated groups in a dose- and duration-dependent manners. The increased protein level of PARPs and lowered hydroxyl methyl-glutaryl CoA reductase activity were significantly reversed after PEE treatment. CONCLUSIONS This study concludes that PEE might be a suitable and viable regimen against diabetic complications in rats. GRAPHICAL ABSTRACT
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Affiliation(s)
- Regina Ngozi Ugbaja
- Department of Biochemistry, Federal University of Agriculture, Abeokuta, P.M.B 2240, Nigeria
- Faculty of Sciences, Department of Chemical Sciences (Biochemistry Programme), Augustine University, Ilara-Epe, Lagos State Nigeria
| | - Tolulope Peter Fatokun
- Department of Biochemistry, Federal University of Agriculture, Abeokuta, P.M.B 2240, Nigeria
| | - Dorcas Ibukun Akinloye
- Department of Biochemistry, Federal University of Agriculture, Abeokuta, P.M.B 2240, Nigeria
| | - Adewale Segun James
- Department of Biochemistry, Federal University of Agriculture, Abeokuta, P.M.B 2240, Nigeria
| | - Oluseye Olusegun Onabanjo
- Department of Nutrition and Dietetics, Federal University of Agriculture, P.M.B 2240, Abeokuta, Nigeria
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27
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Doğanlar ZB, Doğanlar O, Kurtdere K, Güçlü H, Chasan T, Turgut E. Melatonin prevents blood-retinal barrier breakdown and mitochondrial dysfunction in high glucose and hypoxia-induced in vitro diabetic macular edema model. Toxicol In Vitro 2021; 75:105191. [PMID: 33962019 DOI: 10.1016/j.tiv.2021.105191] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/29/2021] [Accepted: 05/02/2021] [Indexed: 12/31/2022]
Abstract
Diabetic macular edema (DME) is a leading cause of blindness in diabetic retinopathy. Prolonged hyperglycemia plus hypoxia contributes to DME pathogenesis. Retinal pigmented epithelial cells comprise the outer blood-retinal barrier and are essential for maintaining physiological functioning of the retina. Melatonin acts as an antioxidant and regulator of mitochondrial bioenergetics and has a protective effect against ocular diseases. However, the role of mitochondrial dysfunction and the therapeutic potential of melatonin in DME remain largely unexplored. Here, we used an in vitro model of DME to investigate blood-retinal barrier integrity and permeability, angiogenesis, mitochondrial dynamics, and apoptosis signaling to evaluate the potential protective efficacy of melatonin in DME. We found that melatonin prevents cell hyper-permeability and outer barrier breakdown by reducing HIF-1α, HIF-1β and VEGF and VEGF receptor gene expression. In addition, melatonin reduced the expression of genes involved in mitochondrial fission (DRP1, hFis1, MIEF2, MFF), mitophagy (PINK, BNip3, NIX), and increased the expression of genes involved in mitochondrial biogenesis (PGC-1α, NRF2, PPAR-γ) to maintain mitochondrial homeostasis. Moreover, melatonin prevented apoptosis of retinal pigmented epithelial cells. Our results suggest that mitochondrial dysfunction may be involved in DME pathology, and melatonin may have therapeutic value in DME, by targeting signaling in mitochondria.
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Affiliation(s)
- Zeynep Banu Doğanlar
- Trakya University, Faculty of Medicine, Department of Medical Biology, Edirne, Turkey.
| | - Oğuzhan Doğanlar
- Trakya University, Faculty of Medicine, Department of Medical Biology, Edirne, Turkey
| | - Kardelen Kurtdere
- Trakya University, Faculty of Medicine, Department of Medical Biology, Edirne, Turkey
| | - Hande Güçlü
- Trakya University, Faculty of Medicine, Department of Ophthalmology, Edirne, Turkey
| | - Tourkian Chasan
- Trakya University, Faculty of Medicine, Department of Medical Biology, Edirne, Turkey
| | - Esra Turgut
- Trakya University, Faculty of Medicine, Department of Medical Biology, Edirne, Turkey
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28
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Biswas S, Feng B, Chen S, Liu J, Aref-Eshghi E, Gonder J, Ngo V, Sadikovic B, Chakrabarti S. The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2021; 62:20. [PMID: 33724292 PMCID: PMC7980040 DOI: 10.1167/iovs.62.3.20] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
Purpose Diabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the epigenetic implications of HOTAIR in DR, and we investigated such relationships herein. Methods We used HRECs exposed to various glucose concentrations and epigenetic modulators to examine HOTAIR, angiogenic, and DR-related molecular markers. Oxidative stress, angiogenesis, and mitochondrial dysfunction were assessed. Retinal tissues of diabetic rodents and the vitreous humor and serum of patients with proliferative DR were also investigated. Results Hyperglycemia significantly augmented HOTAIR expression in HRECs and promoted angiogenesis, oxidative damage, and mitochondrial aberrations. Similarly, vitreous humor and serum from proliferative DR patients and retinas from diabetic animals demonstrated increased HOTAIR expression compared to non-diabetic controls. HOTAIR knockdown protected against glucose-induced increases of angiogenic and diabetes-associated molecules in the retina. Mechanistically, we showed that HOTAIR exerts its capabilities by preventing oxidative stress and modulating epigenetic pathways involving histone methylation, histone acetylation, DNA methylation, and transcription factors. Conclusions Our findings suggest that HOTAIR is a critical lncRNA in the pathogenesis of DR and may potentially be important for diagnostic and therapeutic targeting.
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Affiliation(s)
- Saumik Biswas
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Biao Feng
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Shali Chen
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Jieting Liu
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Erfan Aref-Eshghi
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - John Gonder
- Department of Ophthalmology, Western University, London, Ontario, Canada
| | - Vy Ngo
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Subrata Chakrabarti
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
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29
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Patrick AT, He W, Madu J, Sripathi SR, Choi S, Lee K, Samson FP, Powell FL, Bartoli M, Jee D, Gutsaeva DR, Jahng WJ. Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome. J Diabetes Metab Disord 2021; 19:829-848. [PMID: 33520806 DOI: 10.1007/s40200-020-00570-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 05/20/2020] [Accepted: 06/10/2020] [Indexed: 02/07/2023]
Abstract
Purpose The current study aims to determine the molecular mechanisms of diabetic retinopathy (DR) using the protein-protein interactome and metabolome map. We examined the protein network of novel biomarkers of DR for direct (physical) and indirect (functional) interactions using clinical target proteins in different models. Methods We used proteomic tools including 2-dimensional gel electrophoresis, mass spectrometry analysis, and database search for biomarker identification using in vivo murine and human model of diabetic retinopathy and in vitro model of oxidative stress. For the protein interactome and metabolome mapping, various bioinformatic tools that include STRING and OmicsNet were used. Results We uncovered new diabetic biomarkers including prohibitin (PHB), dynamin 1, microtubule-actin crosslinking factor 1, Toll-like receptor (TLR 7), complement activation, as well as hypothetical proteins that include a disintegrin and metalloproteinase (ADAM18), vimentin III, and calcium-binding C2 domain-containing phospholipid-binding switch (CAC2PBS) using a proteomic approach. Proteome networks of protein interactions with diabetic biomarkers were established using known DR-related proteome data. DR metabolites were interconnected to establish the metabolome map. Our results showed that mitochondrial protein interactions were changed during hyperglycemic conditions in the streptozotocin-treated murine model and diabetic human tissue. Conclusions Our interactome mapping suggests that mitochondrial dysfunction could be tightly linked to various phases of DR pathogenesis including altered visual cycle, cytoskeletal remodeling, altered lipid concentration, inflammation, PHB depletion, tubulin phosphorylation, and altered energy metabolism. The protein-metabolite interactions in the current network demonstrate the etiology of retinal degeneration and suggest the potential therapeutic approach to treat DR.
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Affiliation(s)
- Ambrose Teru Patrick
- Retina Proteomics Laboratory, Department of Petroleum Chemistry, American University of Nigeria, Yola, Nigeria
| | - Weilue He
- Department of Biomedical Engineering, Michigan Technological University, Houghton, MI USA
| | - Joshua Madu
- Retina Proteomics Laboratory, Department of Petroleum Chemistry, American University of Nigeria, Yola, Nigeria
| | - Srinivas R Sripathi
- Department of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Seulggie Choi
- Division of Vitreous and Retina, Department of Ophthalmology, College of Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Kook Lee
- Division of Vitreous and Retina, Department of Ophthalmology, College of Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Faith Pwaniyibo Samson
- Retina Proteomics Laboratory, Department of Petroleum Chemistry, American University of Nigeria, Yola, Nigeria
| | - Folami L Powell
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA USA
| | - Manuela Bartoli
- Department of Ophthalmology, Augusta University, Augusta, GA USA
| | - Donghyun Jee
- Division of Vitreous and Retina, Department of Ophthalmology, College of Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Diana R Gutsaeva
- Department of Ophthalmology, Augusta University, Augusta, GA USA
| | - Wan Jin Jahng
- Retina Proteomics Laboratory, Department of Petroleum Chemistry, American University of Nigeria, Yola, Nigeria
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Nagayasu M, Imanaka S, Kimura M, Maruyama S, Kobayashi H. Nonhormonal Treatment for Endometriosis Focusing on Redox Imbalance. Gynecol Obstet Invest 2021; 86:1-12. [PMID: 33395684 DOI: 10.1159/000512628] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/26/2020] [Indexed: 11/19/2022]
Abstract
The aim of this review is to investigate the oxidant/antioxidant status and its regulatory mechanisms in patients with endometriosis and to summarize the antioxidant therapy as an alternative to hormonal therapy for endometriosis. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and March 2020. Endometriosis is a chronic inflammatory disease characterized by repeated episodes of hemorrhage. Methemoglobin in repeated hemorrhage produces large amounts of superoxide anion via the autoxidation of hemoglobin. Excessive free-radical production causes redox imbalance, leading to inadequate antioxidant defenses and damage to endometrial cells, but may contribute to endometrial cell growth and survival through activation of various signaling pathways. In addition, to overcome excessive oxidative stress, estradiol participates in the induction of antioxidants such as superoxide dismutase in mitochondria. Several antioxidants that suppress free radicals may be effective in endometriosis-related pain. We searched for 23 compounds and natural substances that could reduce the pain caused by superoxide/reactive oxygen species in basic research and animal models. Next, we built a list of 16 drugs that were suggested to be effective against endometriosis other than hormone therapy in preclinical studies and clinical trials. Of the 23 and 16 drugs, 4 overlapping drugs could be potential candidates for clinically reducing endometriosis-related pain caused by superoxide anion/reactive oxygen species. These drugs include polyphenols (resveratrol and polydatin), dopamine agonists (cabergoline), and statins (simvastatin). However, no randomized controlled trials have evaluated the efficacy of these drugs. In conclusion, this review summarizes the following 2 points: superoxide anion generation by methemoglobin is enhanced in endometriosis, resulting in redox imbalance; and some compounds and natural substances that can suppress free radicals may be effective in endometriosis-related pain. Further randomized clinical trials based on larger series are mandatory to confirm the promising role of antioxidants in the nonhormonal management of endometriosis.
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Affiliation(s)
- Mika Nagayasu
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
| | - Shogo Imanaka
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.,Ms.Clinic MayOne, Kashihara, Japan
| | - Mai Kimura
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
| | - Sachiyo Maruyama
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
| | - Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan, .,Ms.Clinic MayOne, Kashihara, Japan,
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Atale N, Yadav D, Rani V, Jin JO. Pathophysiology, Clinical Characteristics of Diabetic Cardiomyopathy: Therapeutic Potential of Natural Polyphenols. Front Nutr 2020; 7:564352. [PMID: 33344490 PMCID: PMC7744342 DOI: 10.3389/fnut.2020.564352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/27/2020] [Indexed: 12/20/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is an outcome of disturbances in metabolic activities through oxidative stress, local inflammation, and fibrosis, as well as a prime cause of fatality worldwide. Cardiovascular disorders in diabetic individuals have become a challenge in diagnosis and formulation of treatment prototype. It is necessary to have a better understanding of cellular pathophysiology that reveal the therapeutic targets and prevent the progression of cardiovascular diseases due to hyperglycemia. Critical changes in levels of collagen and integrin have been observed in the extracellular matrix of heart, which was responsible for cardiac remodeling in diabetic patients. This review explored the understanding of the mechanisms of how the phytochemicals provide cardioprotection under diabetes along with the caveats and provide future perspectives on these agents as prototypes for the development of drugs for managing DCM. Thus, here we summarized the effect of various plant extracts and natural polyphenols tested in preclinical and cell culture models of diabetic cardiomyopathy. Further, the potential use of selected polyphenols that improved the therapeutic efficacy against diabetic cardiomyopathy is also illustrated.
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Affiliation(s)
- Neha Atale
- Jaypee Institute of Information Technology, Noida, India
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
| | - Vibha Rani
- Jaypee Institute of Information Technology, Noida, India
| | - Jun-O Jin
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, South Korea
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Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6212935. [PMID: 33204397 PMCID: PMC7652615 DOI: 10.1155/2020/6212935] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/13/2020] [Accepted: 07/13/2020] [Indexed: 12/18/2022]
Abstract
Redox-active substances and their combinations, such as of quinone/ascorbate and in particular menadione/ascorbate (M/A; also named Apatone®), attract attention with their unusual ability to kill cancer cells without affecting the viability of normal cells as well as with the synergistic anticancer effect of both molecules. So far, the primary mechanism of M/A-mediated anticancer effects has not been linked to the mitochondria. The aim of our study was to clarify whether this “combination drug” affects mitochondrial functionality specifically in cancer cells. Studies were conducted on cancer cells (Jurkat, Colon26, and MCF7) and normal cells (normal lymphocytes, FHC, and MCF10A), treated with different concentrations of menadione, ascorbate, and/or their combination (2/200, 3/300, 5/500, 10/1000, and 20/2000 μM/μM of M/A). M/A exhibited highly specific and synergistic suppression on cancer cell growth but without adversely affecting the viability of normal cells at pharmacologically attainable concentrations. In M/A-treated cancer cells, the cytostatic/cytotoxic effect is accompanied by (i) extremely high production of mitochondrial superoxide (up to 15-fold over the control level), (ii) a significant decrease of mitochondrial membrane potential, (iii) a decrease of the steady-state levels of ATP, succinate, NADH, and NAD+, and (iv) a decreased expression of programed cell death ligand 1 (PD-L1)—one of the major immune checkpoints. These effects were dose dependent. The inhibition of NQO1 by dicoumarol increased mitochondrial superoxide and sensitized cancer cells to M/A. In normal cells, M/A induced relatively low and dose-independent increase of mitochondrial superoxide and mild oxidative stress, which seems to be well tolerated. These data suggest that all anticancer effects of M/A result from a specific mechanism, tightly connected to the mitochondria of cancer cells. At low/tolerable doses of M/A (1/100-3/300 μM/μM) attainable in cancer by oral and parenteral administration, M/A sensitized cancer cells to conventional anticancer drugs, exhibiting synergistic or additive cytotoxicity accompanied by impressive induction of apoptosis. Combinations of M/A with 13 anticancer drugs were investigated (ABT-737, barasertib, bleomycin, BEZ-235, bortezomib, cisplatin, everolimus, lomustine, lonafarnib, MG-132, MLN-2238, palbociclib, and PI-103). Low/tolerable doses of M/A did not induce irreversible cytotoxicity in cancer cells but did cause irreversible metabolic changes, including: (i) a decrease of succinate and NADH, (ii) depolarization of the mitochondrial membrane, and (iii) overproduction of superoxide in the mitochondria of cancer cells only. In addition, M/A suppressed tumor growth in vivo after oral administration in mice with melanoma and the drug downregulated PD-L1 in melanoma cells. Experimental data suggest a great potential for beneficial anticancer effects of M/A through increasing the sensitivity of cancer cells to conventional anticancer therapy, as well as to the immune system, while sparing normal cells. We hypothesize that M/A-mediated anticancer effects are triggered by redox cycling of both substances, specifically within dysfunctional mitochondria. M/A may also have a beneficial effect on the immune system, making cancer cells “visible” and more vulnerable to the native immune response.
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Velagic A, Qin C, Woodman OL, Horowitz JD, Ritchie RH, Kemp-Harper BK. Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling. Front Pharmacol 2020; 11:727. [PMID: 32508651 PMCID: PMC7248192 DOI: 10.3389/fphar.2020.00727] [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] [Received: 03/01/2020] [Accepted: 05/01/2020] [Indexed: 12/19/2022] Open
Abstract
Diabetes is associated with an increased mortality risk due to cardiovascular complications. Hyperglycemia-induced oxidative stress underlies these complications, leading to an impairment in endogenous nitric oxide (NO•) generation, together with reductions in NO• bioavailability and NO• responsiveness in the vasculature, platelets and myocardium. The latter impairment of responsiveness to NO•, termed NO• resistance, compromises the ability of traditional NO•-based therapeutics to improve hemodynamic status during diabetes-associated cardiovascular emergencies, such as acute myocardial infarction. Whilst a number of agents can ameliorate (e.g. angiotensin converting enzyme [ACE] inhibitors, perhexiline, statins and insulin) or circumvent (e.g. nitrite and sGC activators) NO• resistance, nitroxyl (HNO) donors offer a novel opportunity to circumvent NO• resistance in diabetes. With a suite of vasoprotective properties and an ability to enhance cardiac inotropic and lusitropic responses, coupled with preserved efficacy in the setting of oxidative stress, HNO donors have intact therapeutic potential in the face of diminished NO• signaling. This review explores the major mechanisms by which hyperglycemia-induced oxidative stress drives NO• resistance, and the therapeutic potential of HNO donors to circumvent this to treat cardiovascular complications in type 2 diabetes mellitus.
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Affiliation(s)
- Anida Velagic
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - Chengxue Qin
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - Owen L. Woodman
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - John D. Horowitz
- Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia
| | - Rebecca H. Ritchie
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Barbara K. Kemp-Harper
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
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Reyaz A, Alam S, Chandra K, Kohli S, Agarwal S. Methylglyoxal and soluble RAGE in type 2 diabetes mellitus: Association with oxidative stress. J Diabetes Metab Disord 2020; 19:515-521. [PMID: 32550204 DOI: 10.1007/s40200-020-00543-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/30/2020] [Accepted: 05/07/2020] [Indexed: 01/17/2023]
Abstract
Purpose Methylglyoxal (MGO) and MGO related advance end product (AGE) are thought to contribute to the development of diabetes and its complications. The present study was intended to determine plasma MGO and sRAGE levels in T2DM patients and to assess the relationship between MGO and other parameters, such as sRAGE and oxidative markers. Methods The study was carried out in 100 control and T2DM subjects. Methylglyoxal, sRAGE, HbA1c, and other markers were measured by using a standard protocol and the relationship between variables was analyzed using Spearman's correlation analysis. Results Plasma MGO levels in patients with T2DM (221.1 ± 9.50 ng/mL) were significantly higher than in control subjects (121.1 ± 6.52 ng/mL, P < 0.001). The plasma level of MGO was positively correlated with glycosylated hemoglobin (HbA1c, r = 0.50, P < 0.001). Plasma soluble form of RAGE (sRAGE) was significantly decreased in T2DM subjects (5.3 ± 0.64 ng/mL) as compared to the control group (7.7 ± 0.86 ng/mL, p < 0.05). However, at increased level of glycation (HbA1c > 10%), the sRAGE level was 6.2 ± 0.42 ng/mL and was not statistically significant as compared to control healthy group (> 0.05). Moreover, we have not found any correlation between MGO and other markers (p > 0.05). Conclusions The findings of the present study showed that increased plasma MGO level is significantly associated with the HbA1c levels in T2DM patients. Moreover, the study shows that plasma sRAGE level is significantly augmented at increased level of glycation (HbA1c > 10%) in T2DM patients.
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Affiliation(s)
- Alisha Reyaz
- Department of Biochemistry, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, 110062 New Delhi, India
| | - Sana Alam
- Department of Biochemistry, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, 110062 New Delhi, India
| | - Kailash Chandra
- Department of Biochemistry, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, 110062 New Delhi, India
| | - Sunil Kohli
- Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
| | - Sarita Agarwal
- Department of Biochemistry, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, 110062 New Delhi, India
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Ribeiro-Silva M, Oliveira-Pinto J, Mansilha A. Abdominal aortic aneurysm: a review on the role of oral antidiabetic drugs. INT ANGIOL 2020; 39:330-340. [PMID: 32286765 DOI: 10.23736/s0392-9590.20.04362-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION A paradoxical negative association between diabetes mellitus and abdominal aortic aneurysm (AAA) prevalence and growth is established. However, so far is not possible to determine whether this protection comes from the disease itself or the medication for Diabetes. The aim of this manuscript is to review the association between oral antidiabetic drugs and AAA incidence and growth. EVIDENCE ACQUISITION A search was conducted on PubMed and Scopus databases until December 2019 to identify publications reporting on the association between oral antidiabetic drugs (biguanides/metformin, sulfonylureas(SU), thiazolidinediones(TZD), dipeptidyl-peptidase 4(DPP-4) inhibitors, glucagon-like peptide 1(GLP-1) agonists, sodium-glucose transporter protein-2(SGLT2) inhibitors) and the outcomes AAA incidence and growth. Only data from human studies were considered, with a minimum of 3 months follow-up. EVIDENCE SYNTHESIS Six studies enrolling 25,810 patients were included: one reporting on the AAA risk and five reporting on AAA growth. Metformin prescription was associated with a 28% reduction in AAA occurrence, while SU and TZD were associated with a 18% decrease in AAA risk. Regarding AAA enlargement, results were concordant for a slower expansion rate associated with metformin, with a decrease ranging from -0.30 mm/y to -1.30 mm/y, but not consistent for other antidiabetic drugs. CONCLUSIONS Metformin seems to be associated with a decrease in AAA risk and enlargement rate. Evidence for the other classes is lacking. Studies evaluating the association between oral antidiabetic drugs and AAA progression, independently of the diabetic status, are needed.
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Affiliation(s)
| | - José Oliveira-Pinto
- Department of Angiology and Vascular Surgery, Hospital Center of São João, Porto, Portugal.,Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal.,Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Angiology and Vascular Surgery, Hospital CUF of Porto, Porto, Portugal
| | - Armando Mansilha
- Department of Angiology and Vascular Surgery, Hospital Center of São João, Porto, Portugal.,Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
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The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism. Genes Dev 2020; 34:321-340. [PMID: 32029456 PMCID: PMC7050491 DOI: 10.1101/gad.334284.119] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In this review, Szanto et al. summarize the metabolic regulatory roles of PARP enzymes and their associated pathologies. Poly(ADP-ribose) polymerases (PARPs or ARTDs), originally described as DNA repair factors, have metabolic regulatory roles. PARP1, PARP2, PARP7, PARP10, and PARP14 regulate central and peripheral carbohydrate and lipid metabolism and often channel pathological disruptive metabolic signals. PARP1 and PARP2 are crucial for adipocyte differentiation, including the commitment toward white, brown, or beige adipose tissue lineages, as well as the regulation of lipid accumulation. Through regulating adipocyte function and organismal energy balance, PARPs play a role in obesity and the consequences of obesity. These findings can be translated into humans, as evidenced by studies on identical twins and SNPs affecting PARP activity.
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Adki KM, Kulkarni YA. Potential Biomarkers in Diabetic Retinopathy. Curr Diabetes Rev 2020; 16:971-983. [PMID: 32065092 DOI: 10.2174/1573399816666200217092022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/28/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Diabetic retinopathy is one of the important complications of diabetes. In major cases, diabetic retinopathy is unnoticed until the irreversible damage to eye occurs and leads to blurred vision and, eventually, blindness. OBJECTIVE The pathogenesis and diagnosis of diabetic retinopathy are very complex and not fully understood. Currently, well-established laser techniques and medications are available, but these treatment options have their own shortcomings on biological systems. Biomarkers can help to overcome this problem due to easy, fast and economical options for diagnosis of diabetic retinopathy. METHODS The search terms used were "Diabetic retinopathy", "Biomarkers in diabetic retinopathy", "Novel biomarkers in diabetic retinopathy" and "Potential biomarkers of diabetic retinopathy" by using different scientific resources and databases like EBSCO, ProQuest, PubMed and Scopus. Eligibility criteria included biomarkers involved in diabetic retinopathy in the detectable range. Exclusion criteria included the repetition and duplication of the biomarker in diabetic retinopathy. RESULTS Current review and literature study revealed that biomarkers of diabetic retinopathy can be categorized as inflammatory: tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor- β; antioxidant: nicotinamide adenine dinucleotide phosphate oxidase; nucleic acid: poly ADP ribose polymerase- α, Apelin, Oncofetal; enzyme: ceruloplasmin, protein kinase C; and miscellaneous: erythropoietin. These biomarkers have a great potential in the progression of diabetic retinopathy hence can be used in the diagnosis and management of this debilitating disease. CONCLUSION Above mentioned biomarkers play a key role in the pathogenesis of diabetic retinopathy; hence they can also be considered as potential targets for new drug development.
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Affiliation(s)
- Kaveri M Adki
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (West), Mumbai-400056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (West), Mumbai-400056, India
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Song J, Yang X, Yan LJ. Role of pseudohypoxia in the pathogenesis of type 2 diabetes. HYPOXIA (AUCKLAND, N.Z.) 2019; 7:33-40. [PMID: 31240235 PMCID: PMC6560198 DOI: 10.2147/hp.s202775] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/23/2019] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes is caused by persistent high blood glucose, which is known as diabetic hyperglycemia. This hyperglycemic situation, when not controlled, can overproduce NADH and lower nicotinamide adenine dinucleotide (NAD), thereby creating NADH/NAD redox imbalance and leading to cellular pseudohypoxia. In this review, we discussed two major enzymatic systems that are activated by diabetic hyperglycemia and are involved in creation of this pseudohypoxic condition. One system is aldose reductase in the polyol pathway, and the other is poly (ADP ribose) polymerase. While aldose reductase drives overproduction of NADH, PARP could in contrast deplete NAD. Therefore, activation of the two pathways underlies the major mechanisms of NADH/NAD redox imbalance and diabetic pseudohypoxia. Consequently, reductive stress occurs, followed by oxidative stress and eventual cell death and tissue dysfunction. Additionally, fructose formed in the polyol pathway can also cause metabolic syndrome such as hypertension and nonalcoholic fatty liver disease. Moreover, pseudohypoxia can also lower sirtuin protein contents and induce protein acetylation which can impair protein function. Finally, we discussed the possibility of using nicotinamide riboside, an NAD precursor, as a promising therapeutic agent for restoring NADH/NAD redox balance and for preventing the occurrence of diabetic pseudohypoxia.
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Affiliation(s)
- Jing Song
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
- School of Public Health, Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Xiaojuan Yang
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
- Department of Geriatrics, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Liang-Jun Yan
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
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Palazzo L, Mikolčević P, Mikoč A, Ahel I. ADP-ribosylation signalling and human disease. Open Biol 2019; 9:190041. [PMID: 30991935 PMCID: PMC6501648 DOI: 10.1098/rsob.190041] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/22/2019] [Indexed: 02/06/2023] Open
Abstract
ADP-ribosylation (ADPr) is a reversible post-translational modification of proteins, which controls major cellular and biological processes, including DNA damage repair, cell proliferation and differentiation, metabolism, stress and immune responses. In order to maintain the cellular homeostasis, diverse ADP-ribosyl transferases and hydrolases are involved in the fine-tuning of ADPr systems. The control of ADPr network is vital, and dysregulation of enzymes involved in the regulation of ADPr signalling has been linked to a number of inherited and acquired human diseases, such as several neurological disorders and in cancer. Conversely, the therapeutic manipulation of ADPr has been shown to ameliorate several disorders in both human and animal models. These include cardiovascular, inflammatory, autoimmune and neurological disorders. Herein, we summarize the recent findings in the field of ADPr, which support the impact of this modification in human pathophysiology and highlight the curative potential of targeting ADPr for translational and molecular medicine.
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Affiliation(s)
- Luca Palazzo
- Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy
| | - Petra Mikolčević
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
| | - Andreja Mikoč
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
| | - Ivan Ahel
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK
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Identification and quantification of DNA repair protein poly(ADP ribose) polymerase 1 (PARP1) in human tissues and cultured cells by liquid chromatography/isotope-dilution tandem mass spectrometry. DNA Repair (Amst) 2019; 75:48-59. [PMID: 30743082 DOI: 10.1016/j.dnarep.2019.01.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/31/2019] [Accepted: 01/31/2019] [Indexed: 12/14/2022]
Abstract
Poly(ADP ribose) polymerase 1 (PARP1) is a multifunctional DNA repair protein of the base excision repair pathway and plays a major role in the repair of DNA strand breaks and in replication and transcriptional regulation among other functions. Mounting evidence points to the predictive and prognostic value of PARP1 expression in human cancers. Thus, PARP1 has become an important target in cancer therapy, leading to the development of inhibitors as anticancer drugs. In the past, PARP1 expression levels in tissue samples have generally been estimated by indirect and semi-quantitative immunohistochemical methods. Accurate measurement of PARP1 in normal tissues and malignant tumors of patients will be essential for evaluating PARP1 as a predictive and prognostic biomarker in cancer and other diseases, and for the development and use of its inhibitors in cancer therapy. In this work, we present an approach involving liquid chromatography-isotope-dilution tandem mass spectrometry to positively identify and accurately quantify PARP1 in human tissues and cultured cells. We identified and quantified PARP1 in human normal ovarian tissues and malignant ovarian tumors, and in three pairs of human cell lines, each pair consisting of a normal cell line and its cancerous counterpart. Significantly greater expression of PARP1 was observed in malignant ovarian tissues than in normal ovarian tissues. In the case of one pair of cell lines, the cancerous cell line also exhibited greater expression of PARP1 than in normal cell line. We also show the simultaneous measurement of PARP1 and apurinic/apyrimidinic endonuclease 1 (APE1) in a given protein extract. The approach presented in this work is expected to contribute to the accurate quantitative assessment of PARP1 levels in basic research and clinical studies.
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Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Emerging Biomarkers, Tools, and Treatments for Diabetic Polyneuropathy. Endocr Rev 2019; 40:153-192. [PMID: 30256929 DOI: 10.1210/er.2018-00107] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 08/23/2018] [Indexed: 12/12/2022]
Abstract
Diabetic neuropathy, with its major clinical sequels, notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options. Thus, a better understanding of the underlying pathophysiology is mandatory for translation into new diagnostic and treatment approaches. Improved knowledge about pathogenic pathways implicated in the development of diabetic neuropathy could lead to novel diagnostic techniques that have the potential of improving the early detection of neuropathy in diabetes and prediabetes to eventually embark on new treatment strategies. In this review, we first provide an overview on the current clinical aspects and illustrate the pathogenetic concepts of (pre)diabetic neuropathy. We then describe the biomarkers emerging from these concepts and novel diagnostic tools and appraise their utility in the early detection and prediction of predominantly distal sensorimotor polyneuropathy. Finally, we discuss the evidence for and limitations of the current and novel therapy options with particular emphasis on lifestyle modification and pathogenesis-derived treatment approaches. Altogether, recent years have brought forth a multitude of emerging biomarkers reflecting different pathogenic pathways such as oxidative stress and inflammation and diagnostic tools for an early detection and prediction of (pre)diabetic neuropathy. Ultimately, these insights should culminate in improving our therapeutic armamentarium against this common and debilitating or even life-threatening condition.
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Affiliation(s)
- Gidon J Bönhof
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Munich-Neuherberg, Neuherberg, Partner Düsseldorf, Düsseldorf, Germany.,Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Alexander Strom
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Munich-Neuherberg, Neuherberg, Partner Düsseldorf, Düsseldorf, Germany
| | - Nikolaos Papanas
- Second Department of Internal Medicine, Diabetes Center, Diabetic Foot Clinic, Democritus University of Thrace, Alexandroupolis, Greece
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Munich-Neuherberg, Neuherberg, Partner Düsseldorf, Düsseldorf, Germany.,Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Munich-Neuherberg, Neuherberg, Partner Düsseldorf, Düsseldorf, Germany.,Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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Fan Y, Yan G, Liu F, Rong J, Ma W, Yang D, Yu Y. Potential role of poly (ADP-ribose) polymerase in delayed cerebral vasospasm following subarachnoid hemorrhage in rats. Exp Ther Med 2019; 17:1290-1299. [PMID: 30680005 PMCID: PMC6327579 DOI: 10.3892/etm.2018.7073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 11/14/2018] [Indexed: 01/13/2023] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) serves a key role in several neurological disorders, however, the specific role of PARP in delayed cerebral vasospasm (DCVS) following subarachnoid hemorrhage (SAH) remains unclear. The present study was conducted to clarify the possible mechanism of PARP in DCVS with the treatment of 3-aminobenzamide (3-AB), a PARP inhibitor. In the preliminary experiment, an internal carotid artery puncture SAH model, a cisterna magna double injection SAH model and prechiasmatic cistern single injection SAH model were compared with respect to mortality and neurobehavioral test results. The prechiasmatic cistern single injection SAH model was chosen to induce DCVS in the formal experiment. In the formal experiment, a total of 96 Sprague Dawley rats were randomly allocated into the sham group, the SAH group and the SAH+3-AB group and then each group was further subdivided into days 3, 5, 7 and 14 post-SAH subgroups (n=8 for each subgroup). The prechiasmatic cistern single injection SAH model was established to induce DCVS. Neurobehavioral testing and HE staining were conducted to evaluate the degree of cerebral vasospasm. PARP activity was assessed by ELISA and immunohistochemistry. An electrophoretic mobility shift assay was used to detect nuclear factor (NF)-κB DNA-binding activity. The expression of monocyte chemotactic protein 1 (MCP-1) and C-reactive protein (CRP) were measured by western blotting. Cerebral vasospasm occurred following SAH and became most severe on around day 7 post-SAH. NF-κB activity, PARP activity, the expression of MCP-1 and CRP exhibited a similar time course to cerebral vasospasm. Treatment with 3-AB alleviated the degree of cerebral vasospasm. NF-κB activity, PARP activity and the expression of MCP-1 and CRP were also suppressed by 3-AB treatment. In conclusion, PARP may serve an important role in regulating the inflammatory response and ultimately contribute to DCVS. Therefore 3-AB may be a potential therapeutic agent for DCVS.
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Affiliation(s)
- Yameng Fan
- Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Ge Yan
- Department of Medical Image, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Furong Liu
- Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jie Rong
- Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Wenxia Ma
- Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Danrong Yang
- Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yan Yu
- Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Flores-Tamez V, Escalante B, Rios A. Peroxynitrite-Induced Intracellular Ca2+ Depression in Cardiac Myocytes: Role of Sarco/Endoplasmic Reticulum Ca2+ Pump. Folia Biol (Praha) 2019; 65:237-245. [PMID: 32362307 DOI: 10.14712/fb2019065050237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Several studies have shown that peroxynitrite (ONOO-), formed upon the reaction of •NO and O2-, is increased in many cardiovascular diseases and is detrimental to myocardial function. Proteins associated with Ca2+ homeostasis regulation in the heart may be involved in these effects. Thus, the aim of this study was to elucidate the mechanisms associated with ONOO--induced effects. We evaluated [Ca2+]i regulation, sarco/endoplasmic reticulum Ca2+- binding proteins, and phosphorylation levels of the ryanodine receptor in isolated rat myocytes. Electrical field-induced intracellular Ca2+ transients and contractions were recorded simultaneously. Myocytes superfused with 3-morpholinosydnonimine N-ethylcarbamide (SIN-1), an ONOO- donor, decreased the amplitude of Ca2+ transients and contraction in a dose-response (1-200 μM) manner. Similarly, SIN-1 increased half-time decay in a concentration-dependent manner. Co-infusion of the ONOO- donor with FeTMPyP (1 μM), an ONOO- decomposition catalyst, inhibited the effects induced by ONOO-. Impaired sarcoplasmic reticulum Ca2+ uptake caused by ONOO- (SIN-1 200 μM) was confirmed by a reduction of caffeine-evoked Ca2+ release along with prolongation of the half-time decay. Surprisingly, ONOO- induced a spontaneous Ca2+ transient that started at the beginning of the relaxation phase and was inhibited by tetracaine. Also, reduced phosphorylation at the ryanodine receptor 2 (RyR2)-Ser-2814 site was observed. In conclusion, deficient sarco/endoplasmic reticulum Ca2+-ATPase-mediated Ca2+ uptake concomitant with augmented Ca2+ release by RyR2 in myocytes may be associated with modification of myocyte Ca2+ handling by ONOO-. Thus, development of cardiac failure in diabetes, nephropathy, or hypertension may be related with elevated ONOO- in cardiac tissue.
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Affiliation(s)
- V Flores-Tamez
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, PIIT, Apodaca NL, México
| | - B Escalante
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, PIIT, Apodaca NL, México
- Universidad de Monterrey, San Pedro Garza García, NL, México
| | - A Rios
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, PIIT, Apodaca NL, México
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Surikow SY, Nguyen TH, Stafford I, Chapman M, Chacko S, Singh K, Licari G, Raman B, Kelly DJ, Zhang Y, Waddingham MT, Ngo DT, Bate AP, Chua SJ, Frenneaux MP, Horowitz JD. Nitrosative Stress as a Modulator of Inflammatory Change in a Model of Takotsubo Syndrome. JACC Basic Transl Sci 2018; 3:213-226. [PMID: 30062207 PMCID: PMC6058954 DOI: 10.1016/j.jacbts.2017.10.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 10/08/2017] [Accepted: 10/10/2017] [Indexed: 10/27/2022]
Abstract
Previous studies have shown that patients with Takotsubo syndrome (TS) have supranormal nitric oxide signaling, and post-mortem studies of TS heart samples revealed nitrosative stress. Therefore, we first showed in a female rat model that isoproterenol induces TS-like echocardiographic changes, evidence of nitrosative stress, and consequent activation of the energy-depleting enzyme poly(ADP-ribose) polymerase-1. We subsequently showed that pre-treatment with an inhibitor of poly(ADP-ribose) polymerase-1 ameliorated contractile abnormalities. These findings thus add to previous reports of aberrant β-adrenoceptor signaling (coupled with nitric oxide synthase activation) to elucidate mechanisms of impaired cardiac function in TS and point to potential methods of treatment.
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Key Words
- 3AB, 3-aminobenzamide
- ANOVA, analysis of variance
- ISO, isoproterenol
- LV, left ventricular
- NFκB, nuclear factor kappa B
- NO, nitric oxide
- NOS, nitric oxide synthase
- NT, nitrotyrosine
- O2–, superoxide
- ONOO–, peroxynitrite
- PAR, poly(ADP-ribose)
- PARP, poly(ADP-ribose) polymerase
- TS, Takotsubo syndrome
- TXNIP, thioredoxin-interacting protein
- Takotsubo cardiomyopathy
- myocardial inflammation
- oxidative stress
- poly(ADP-ribose) polymerase-1
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Affiliation(s)
- Sven Y Surikow
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia.,Basil Hetzel Institute, Adelaide, South Australia, Australia
| | - Thanh H Nguyen
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia.,Basil Hetzel Institute, Adelaide, South Australia, Australia
| | - Irene Stafford
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
| | - Matthew Chapman
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
| | - Sujith Chacko
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
| | - Kuljit Singh
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia.,Basil Hetzel Institute, Adelaide, South Australia, Australia
| | - Giovanni Licari
- Basil Hetzel Institute, Adelaide, South Australia, Australia
| | - Betty Raman
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia.,Basil Hetzel Institute, Adelaide, South Australia, Australia
| | - Darren J Kelly
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
| | - Yuan Zhang
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
| | - Mark T Waddingham
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
| | - Doan T Ngo
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
| | - Alexander P Bate
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
| | - Su Jen Chua
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
| | | | - John D Horowitz
- The Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia.,Basil Hetzel Institute, Adelaide, South Australia, Australia
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45
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Affiliation(s)
- James E Novak
- Henry Ford Hospital, Wayne State University, Detroit, MI
| | - Jerry Yee
- Henry Ford Hospital, Wayne State University, Detroit, MI
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Korkmaz-Icöz S, Radovits T, Loganathan S, Li S, Ruppert M, Benke K, Brlecic P, Szabó C, Karck M, Szabó G. Prolonging hypothermic ischaemic cardiac and vascular storage by inhibiting the activation of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase. Eur J Cardiothorac Surg 2018; 51:829-835. [PMID: 28204209 DOI: 10.1093/ejcts/ezw426] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 12/06/2016] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Heart transplantation is the standard treatment in end-stage heart failure and at shortage of cardiac allografts is its major limiting factor. Striving to optimize the use of this limited resource, the aspect that long distance procurement may increase the available donor pool must be taken into consideration. As poly(ADP-ribose)polymerase (PARP)-activation has been identified as a key pathway of reperfusion injury, we assessed the hypothesis that its inhibition would allow an extension of cold preservation time and protect the graft against ischaemia/reperfusion injury. METHODS Hearts from donor rats were explanted, stored in a preservation solution (Custodiol) at 4 °C for 4 h or 8 h, and heterotopically transplanted. A vehicle or the PARP-inhibitor, INO-1001 (5 mg/kg), was administered during the reperfusion period. We evaluated post-transplant graft function with a Millar micromanometer at different left-ventricular volumes. Additionally, in organ bath experiments the effect of PARP-inhibition on endothelium-dependent and -independent vasorelaxation was evaluated after long-term cold ischaemic storage/warm reperfusion. RESULTS PARP-inhibition resulted in a better systolic functional recovery of grafts submitted to 4 h and 8 h ischaemia. Furthermore, INO-1001 decreased the left-ventricular end-diastolic pressure after 8 h of ischaemia. Coronary blood flow was significantly higher after PARP-inhibition in comparison to controls. Endothelium-dependent vasorelaxation was significantly better in the INO-1001-groups than in the vehicle-treated transplant groups. After 24-h hypothermic storage, treatment of aortic ring with INO-1001 during reoxygenation significantly improved endothelial dysfunction. CONCLUSIONS By inhibiting the PARP activation, INO-1001 can protect the graft and endothelium from the injury that is caused by prolonged cold myocardial ischaemia/reperfusion, thereby improving post-transplant graft function.
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Affiliation(s)
- Sevil Korkmaz-Icöz
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Sivakkanan Loganathan
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.,Department of Anesthesiology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Shiliang Li
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Mihály Ruppert
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.,Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Kálmán Benke
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Paige Brlecic
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Csaba Szabó
- Department of Anesthesiology, University of Texas Medical Branch Galveston, Galveston, TX, USA
| | - Matthias Karck
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Gábor Szabó
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany
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Wang Z, Yuan S, Li Y, Zhang Z, Xiao W, Tang D, Ye K, Liu Z, Wang C, Zheng Y, Nie H, Chen H. Regulation on SIRT1-PGC-1α/Nrf2 pathway together with selective inhibition of aldose reductase makes compound hr5F a potential agent for the treatment of diabetic complications. Biochem Pharmacol 2018; 150:54-63. [PMID: 29371030 DOI: 10.1016/j.bcp.2018.01.034] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 01/18/2018] [Indexed: 10/18/2022]
Abstract
(R,E)-N-(3-(2-acetamido-3-(benzyloxy) propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide (hr5F) was design-synthesized based on bioactivity focus strategy as a potential agent to treat diabetic complicates. With in vitro enzyme assay, it is confirmed that hr5F is an effective ALR2 inhibitor with IC50 value of 2.60 ± 0.15 nM, and selectivity index of 86.0 over ALR1, which is a little bit better than the reference Epalrestat (Epa). hr5F inhibits the increase of ALR2 enzyme activity and expression in human lens epithelial cells (HLECs) induced by high glucose. By applying western blot, it was found that hr5F alleviates the high glucose-induced superoxide overproduction insults by regulating SIRT1-PGC-1α/Nrf2 pathway, together with regulating NRF-1, mtTFA, Bax/Bcl-2 to ameliorate cell apoptosis. The in vivo effects of hr5F on short term streptozocin (STZ)-induced diabetic mice confirm the same functions disclosed in vitro. All the evidences support that hr5F may serve as a promising agent in the treatment of diabetic complications with close efficacy and broader indication than the reference Epa.
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Affiliation(s)
- Zhihua Wang
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Sheng Yuan
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China
| | - Yanbing Li
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China
| | - Zhe Zhang
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Wei Xiao
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Dan Tang
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Kaihe Ye
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Zhijun Liu
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Congcong Wang
- College of Agriculture, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PR China
| | - Yixiong Zheng
- College of Agriculture, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PR China
| | - Hong Nie
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China.
| | - Heru Chen
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China.
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Ahmad W, Ijaz B, Shabbiri K, Ahmed F, Rehman S. Oxidative toxicity in diabetes and Alzheimer's disease: mechanisms behind ROS/ RNS generation. J Biomed Sci 2017; 24:76. [PMID: 28927401 PMCID: PMC5606025 DOI: 10.1186/s12929-017-0379-z] [Citation(s) in RCA: 218] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 09/05/2017] [Indexed: 02/07/2023] Open
Abstract
Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer’s disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.
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Affiliation(s)
- Waqar Ahmad
- School of Biological Sciences, University of Queensland, Brisbane, 4072, Australia.
| | - Bushra Ijaz
- Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig, Lahore, 54000, Pakistan
| | - Khadija Shabbiri
- School of Biological Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Fayyaz Ahmed
- Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig, Lahore, 54000, Pakistan
| | - Sidra Rehman
- COMSATS Institute of Information Technology Abbottabad, Abbottabad, 22010, Pakistan
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Chadha N, Silakari O. Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications. J Mol Graph Model 2017; 76:412-418. [DOI: 10.1016/j.jmgm.2017.07.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 07/18/2017] [Accepted: 07/19/2017] [Indexed: 01/20/2023]
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50
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Wu J, Jin Z, Yan LJ. Redox imbalance and mitochondrial abnormalities in the diabetic lung. Redox Biol 2017; 11:51-59. [PMID: 27888691 PMCID: PMC5124358 DOI: 10.1016/j.redox.2016.11.003] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 11/02/2016] [Indexed: 12/21/2022] Open
Abstract
Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD+ redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD+ content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD+ dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD+ redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes.
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Affiliation(s)
- Jinzi Wu
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Zhen Jin
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Liang-Jun Yan
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
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