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Mahdavifard S, Malekzadeh HR. Symbiotic anti-oxidant, anti-glycation, and anti-inflammatory qualities of a combination of thiamine and niacin protected type-2 diabetic male rats against both macro and micro-vascular complications. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2025; 28:98-104. [PMID: 39877627 PMCID: PMC11771336 DOI: 10.22038/ijbms.2024.77553.16771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 08/11/2024] [Indexed: 01/31/2025]
Abstract
Objectives Increased nuclear factor (NF-kβ) and carbonyl stress due to decreased glyoxalase-1 activity (Glo-I) contribute significantly to insulin resistance and vascular complications. Therefore, we aimed to study the impact of the combination of thiamine and niacin on hepatic NF-kβ signaling, metabolic profile, and Glo-I activity in male rats with type-2 diabetes (T2DM). Materials and Methods Forty male rats were divided equally into five groups: control, diabetic, diabetic treated with thiamine (180 mg/l in drinking water), niacin (180 mg/l), and a combination of both. The treated groups received the treatments daily in drinking water for two months. T2DM was induced using a combination of nicotinamide and alloxan. Metabolic profile and renal dysfunction parameters were assessed. Additionally, various glycation, oxidative stress, and inflammatory markers were measured. Results The treated group with both vitamins showed the lowest blood sugar and insulin resistance indices, cardiovascular indices, renal dysfunction parameters, hepatic NF-kβ expression, oxidative stress, inflammatory and glycation markers, and the highest anti-oxidant and anti-glycation markers, β cell activity, and insulin sensitivity. Thiamine exhibited more anti-inflammatory activity than niacin in diabetic rats, while niacin demonstrated stronger anti-oxidant activity (P<0.001). Conclusion The combined use of vitamins had a more beneficial impact on macro and microvascular complications in diabetes than each alone, attributed to their higher anti-oxidant, anti-inflammatory, and anti-glycation characteristics. The vitamins also had a more corrective effect on glucose-lipid metabolism, insulin sensitivity, and renal function through a stronger lowering effect on hepatic NF-kβ expression.
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Affiliation(s)
- Sina Mahdavifard
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Ardabil University of Medical Sciences, Ardabil, Iran
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2
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Wu Q, Zhu J, Zhang X, Xu X, Luo D, Lin Y, Yan M, Song Y. The antioxidant effect of tetrahedral framework nucleic acid-based delivery of small activating RNA targeting DJ-1 on retinal oxidative stress injury. Cell Prolif 2024; 57:e13635. [PMID: 38594962 PMCID: PMC11294416 DOI: 10.1111/cpr.13635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 04/11/2024] Open
Abstract
Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the world's leading causes of blindness. The retinal pigment epithelium (RPE) and vascular endothelial cell exposed to oxidative stress is the major cause of AMD and DR. DJ-1, an important endogenous antioxidant, its overexpression is considered as a promising antioxidant treatment for AMD and DR. Here, we modified the tetrahedral frame nucleic acids (tFNAs) with DJ-1 saRNAs as a delivery system, and synthesized a novel nanocomplex (tFNAs-DJ-1 saRNAs). In vitro studies show that tFNAs-DJ-1 saRNAs can efficiently transfer DJ-1 saRNAs to human umbilical vein endothelial cells (HUVECs) and ARPE-19s, and significantly increased their cellular DJ-1 level. Reactive oxygen species expression in H2O2-treated HUVECs and ARPE-19s were decreased, cell viability was enhanced and cell apoptosis were inhibited when tFNAs-DJ-1 saRNAs were delivered. Moreover, tFNAs-DJ-1 saRNAs preserved mitochondrial structure and function under oxidative stress conditions. In the aspect of molecular mechanism, tFNAs-DJ-1 saRNAs activated Erk and Nrf2 pathway, which might contribute to its protective effects against oxidative stress damage. To conclude, this study shows the successfully establishment of a simple but effective delivery system of DJ-1 saRNAs associated with antioxidant effects in AMD and DR, which may be a promising agent for future treatment in oxidative stress-related retinal disorders.
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Affiliation(s)
- Qiaowei Wu
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Jingyi Zhu
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Xianggui Zhang
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Xiaoxiao Xu
- Innovative Institute of Chinese Medicine and PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Delun Luo
- Innovative Institute of Chinese Medicine and PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Yunfeng Lin
- Department of Maxillofacial Surgery, State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyChengduChina
| | - Ming Yan
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Yanping Song
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
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3
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Bejarano E, Domenech-Bendaña A, Avila-Portillo N, Rowan S, Edirisinghe S, Taylor A. Glycative stress as a cause of macular degeneration. Prog Retin Eye Res 2024; 101:101260. [PMID: 38521386 PMCID: PMC11699537 DOI: 10.1016/j.preteyeres.2024.101260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/08/2024] [Accepted: 03/11/2024] [Indexed: 03/25/2024]
Abstract
People are living longer and rates of age-related diseases such as age-related macular degeneration (AMD) are accelerating, placing enormous burdens on patients and health care systems. The quality of carbohydrate foods consumed by an individual impacts health. The glycemic index (GI) is a kinetic measure of the rate at which glucose arrives in the blood stream after consuming various carbohydrates. Consuming diets that favor slowly digested carbohydrates releases sugar into the bloodstream gradually after consuming a meal (low glycemic index). This is associated with reduced risk for major age-related diseases including AMD, cardiovascular disease, and diabetes. In comparison, consuming the same amounts of different carbohydrates in higher GI diets, releases glucose into the blood rapidly, causing glycative stress as well as accumulation of advanced glycation end products (AGEs). Such AGEs are cytotoxic by virtue of their forming abnormal proteins and protein aggregates, as well as inhibiting proteolytic and other protective pathways that might otherwise selectively recognize and remove toxic species. Using in vitro and animal models of glycative stress, we observed that consuming higher GI diets perturbs metabolism and the microbiome, resulting in a shift to more lipid-rich metabolomic profiles. Interactions between aging, diet, eye phenotypes and physiology were observed. A large body of laboratory animal and human clinical epidemiologic data indicates that consuming lower GI diets, or lower glycemia diets, is protective against features of early AMD (AMDf) in mice and AMD prevalence or AMD progression in humans. Drugs may be optimized to diminish the ravages of higher glycemic diets. Human trials are indicated to determine if AMD progression can be retarded using lower GI diets. Here we summarized the current knowledge regarding the pathological role of glycative stress in retinal dysfunction and how dietary strategies might diminish retinal disease.
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Affiliation(s)
- Eloy Bejarano
- Department of Biomedical Sciences, School of Health Sciences and Veterinary School, Universidad Cardenal Herrera-CEU, CEU Universities, Valencia, Spain
| | - Alicia Domenech-Bendaña
- Department of Biomedical Sciences, School of Health Sciences and Veterinary School, Universidad Cardenal Herrera-CEU, CEU Universities, Valencia, Spain
| | | | - Sheldon Rowan
- JM USDA Human Nutrition Research Center on Aging at Tufts University, United States
| | - Sachini Edirisinghe
- Tufts University Friedman School of Nutrition Science and Policy, United States
| | - Allen Taylor
- Tufts University Friedman School of Nutrition Science and Policy, United States.
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4
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Liang H, Ren Y, Huang Y, Xie X, Zhang M. Treatment of diabetic retinopathy with herbs for tonifying kidney and activating blood circulation: A review of pharmacological studies. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118078. [PMID: 38513781 DOI: 10.1016/j.jep.2024.118078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 03/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes. Chinese medicine believes that kidney deficiency and blood stasis are significant pathogenesis of DR. A characteristic therapeutic approach for this pathogenesis is the kidney-tonifying and blood-activating method. By literature retrieval from several databases, we methodically summarized the commonly used kidney-tonifying and blood-activating herbs for treating DR, including Lycii Fructus, Rehmanniane Radix Praeparata, and Corni Fructus with the function of nourishing kidney; Salvia Miltiorrhizae Radix et Rhizoma with the function of enhancing blood circulation; Rehmanniae Radix with the function of nourishing kidney yin; and Astragali Radix with the function of tonifying qi. It has been demonstrated that these Chinese herbs described above, by tonifying the kidney and activating blood circulation, significantly improve the course of DR. AIM OF THE STUDY Through literature research, to gain a thorough comprehension of the pathogenesis of DR. Simultaneously, through the traditional application analysis, modern pharmacology research and network pharmacology analysis of kidney-tonifying and blood-activating herbs, to review the effectiveness and advantages of kidney-tonifying and blood-activating herbs in treating DR comprehensively. MATERIALS AND METHODS PubMed, the China National Knowledge Infrastructure (CNKI), and Wanfang Data were used to filter the most popular herbs for tonifying kidney and activating blood in the treatment of DR. The search terms were "diabetic retinopathy" and "tonifying kidney and activating blood". Mostly from 2000 to 2023. Network pharmacology was applied to examine the key active components and forecast the mechanisms of kidney-tonifying and blood-activating herbs in the treatment of DR. RESULTS Kidney deficiency and blood stasis are the pathogenesis of DR, and the pathogenesis is linked to oxidative stress, inflammation, hypoxia, and hyperglycemia. Scientific data and network pharmacology analysis have demonstrated the benefit of tonifying kidney and activating blood herbs in treating DR through several channels, multiple components, and multiple targets. CONCLUSIONS This review first presents useful information for subsequent research into the material foundation and pharmacodynamics of herbs for tonifying kidney and activating blood, and offers fresh insights into the treatment of DR.
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Affiliation(s)
- Huan Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yuan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yuxia Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xuejun Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, China.
| | - Mei Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Alhujaily M. Molecular Assessment of Methylglyoxal-Induced Toxicity and Therapeutic Approaches in Various Diseases: Exploring the Interplay with the Glyoxalase System. Life (Basel) 2024; 14:263. [PMID: 38398772 PMCID: PMC10890012 DOI: 10.3390/life14020263] [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: 12/16/2023] [Revised: 01/31/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
This comprehensive exploration delves into the intricate interplay of methylglyoxal (MG) and glyoxalase 1 (GLO I) in various physiological and pathological contexts. The linchpin of the narrative revolves around the role of these small molecules in age-related issues, diabetes, obesity, cardiovascular diseases, and neurodegenerative disorders. Methylglyoxal, a reactive dicarbonyl metabolite, takes center stage, becoming a principal player in the development of AGEs and contributing to cell and tissue dysfunction. The dual facets of GLO I-activation and inhibition-unfold as potential therapeutic avenues. Activators, spanning synthetic drugs like candesartan to natural compounds like polyphenols and isothiocyanates, aim to restore GLO I function. These molecular enhancers showcase promising outcomes in conditions such as diabetic retinopathy, kidney disease, and beyond. On the contrary, GLO I inhibitors emerge as crucial players in cancer treatment, offering new possibilities in diseases associated with inflammation and multidrug resistance. The symphony of small molecules, from GLO I activators to inhibitors, presents a nuanced understanding of MG regulation. From natural compounds to synthetic drugs, each element contributes to a molecular orchestra, promising novel interventions and personalized approaches in the pursuit of health and wellbeing. The abstract concludes with an emphasis on the necessity of rigorous clinical trials to validate these findings and acknowledges the importance of individual variability in the complex landscape of health.
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Affiliation(s)
- Muhanad Alhujaily
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
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6
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Yeung AM, Huang J, Nguyen KT, Xu NY, Hughes LT, Agrawal BK, Ejskjaer N, Klonoff DC. Painful Diabetic Neuropathy: The Need for New Approaches. J Diabetes Sci Technol 2024; 18:159-167. [PMID: 36305521 PMCID: PMC10899841 DOI: 10.1177/19322968221132252] [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] [Indexed: 11/16/2022]
Abstract
Painful diabetic neuropathy is a common vexing problem for people with diabetes and a costly problem for society. The pathophysiology is not well understood, and no safe and effective mechanistically-based treatment has been identified. Poor glycemic control is a risk factor for painful diabetic neuropathy. Excessive intraneuronal glucose in people with diabetes can be shunted away from physiological glycolysis into multiple pathological pathways associated with neuropathy and pain. The first three treatments that are traditionally offered consist of risk factor reduction, lifestyle modifications, and pharmacological therapy, which includes only three drugs that are approved for this indication by the United States Food and Drug Administration. All of these traditional treatments are often inadequate for relieving neuropathic pain, and thus, new approaches are needed. Modern devices based on neuromodulation technology, which act directly on the nervous system, have been recently cleared by the United States Food and Drug Administration for painful diabetic neuropathy and offer promise as next-in-line therapy when traditional therapies fail.
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Affiliation(s)
| | | | | | - Nicole Y. Xu
- Diabetes Technology Society, Burlingame, CA, USA
| | - Lorenzo T. Hughes
- Balance Health, San Francisco, CA, USA
- Mills-Peninsula Medical Center, Burlingame, CA, USA
| | | | - Niels Ejskjaer
- Steno Diabetes Center North Denmark and Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - David C. Klonoff
- Diabetes Technology Society, Burlingame, CA, USA
- Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA, USA
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Eissa RG, Eissa NG, Eissa RA, Diab NH, Abdelshafi NA, Shaheen MA, Elsabahy M, Hammad SK. Oral proniosomal amitriptyline and liraglutide for management of diabetic neuropathy: Exceptional control over hyperglycemia and neuropathic pain. Int J Pharm 2023; 647:123549. [PMID: 37890645 DOI: 10.1016/j.ijpharm.2023.123549] [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: 06/14/2023] [Revised: 09/19/2023] [Accepted: 10/23/2023] [Indexed: 10/29/2023]
Abstract
Exploitation of nanocarriers provides a compartment for enclosing drugs to protect them from degradation and potentiate their therapeutic efficiency. In the current study, amitriptyline- and liraglutide-loaded proniosomes were constructed for management of diabetic neuropathy, a serious complication associated with diabetes, that triggers spontaneous pain in patients and results in impaired quality of life. The developed therapeutic proniosomes were extensively characterized via dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and Fourier transform-infrared spectroscopy. High entrapment efficiency could be attained for both drugs in the proniosomes, and the reconstituted amitriptyline- and liraglutide-loaded niosomes possessed spherical morphology and particle sizes of 585.3 nm and 864.4 nm, respectively. In a diabetic neuropathy rat model, oral administration of the developed amitriptyline- and liraglutide-loaded proniosomes significantly controlled blood glucose levels, reduced neuropathic pain, oxidative stress and inflammatory markers, and improved histological structure of the sciatic nerve as compared to the oral and subcutaneous administration of amitriptyline and liraglutide, respectively. Loading of the tricyclic antidepressant amitriptyline and the antidiabetic peptide liraglutide into proniosomes resulted in exceptional control over hyperglycemia and neuropathic pain, and thus could provide an auspicious delivery system for management of neuropathic pain and control of blood glucose levels.
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Affiliation(s)
- Rana G Eissa
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Noura G Eissa
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Badr University in Cairo Research Center, Badr University in Cairo, Badr City, Cairo 11829, Egypt
| | - Rana A Eissa
- Badr University in Cairo Research Center, Badr University in Cairo, Badr City, Cairo 11829, Egypt
| | - Nadeen H Diab
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Nahla A Abdelshafi
- Department of Pharmaceutical Analytical Chemistry, School of Pharmacy, Badr University in Cairo, Badr City, Cairo 11829, Egypt
| | - Mohamed A Shaheen
- Department of Histology & Cell Biology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mahmoud Elsabahy
- Badr University in Cairo Research Center, Badr University in Cairo, Badr City, Cairo 11829, Egypt; Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
| | - Sally K Hammad
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
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8
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Bora S, Adole PS, Vinod KV, Pillai AA, Ahmed S. The genetic polymorphisms and activity of glyoxalase 1 as a risk factor for acute coronary syndrome in South Indians with type 2 diabetes mellitus. Gene 2023; 885:147701. [PMID: 37572800 DOI: 10.1016/j.gene.2023.147701] [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: 06/26/2023] [Revised: 07/13/2023] [Accepted: 08/08/2023] [Indexed: 08/14/2023]
Abstract
OBJECTIVE The individuals' genetic traits predispose them to a higher or lower risk of Type 2 diabetes mellitus (T2DM) and its complications, for example, acute coronary syndrome (ACS). As carbonyl stress is responsible for the pathogenesis and complications of T2DM, and glyoxalase 1 (GLO1) is the most crucial determinant of carbonyl stress, the study aimed to explore the association between GLO1 gene polymorphism, GLO1 activity in red blood cell (RBC), plasma methylglyoxal (MG) levels, and ACS risk in South Indian T2DM patients. METHODS A total of 150 T2DM patients with ACS as cases and 150 T2DM patients without ACS as controls were recruited in a case-control study. The rs4746, rs1049346 and rs1130534 of the GLO1 gene were analysed using TaqMan allele discrimination assay. The RBC GLO1 activity and plasma MG levels were measured. RESULTS Significantly lower RBC GLO1 activity and higher plasma MG levels were found in cases compared to controls (p < 0.001 and p = 0.008, respectively). The genotype and allele frequencies of rs1049346 significantly differed between cases and controls (p < 0.001). For rs1130534 and rs1049346, no significant difference was found. For rs1049346, the TT and CC genotypes were associated with higher (p = 0.002) and lower (p = 0.001) ACS risk, respectively, in various genetic models. The TT genotype of rs1049346 was associated with lower RBC GLO1 activity (p = 0.004) and higher MG level (p = 0.010). In haplotype analysis, higher ACS susceptibility with the TAT haplotype (p < 0.001) and lower ACS susceptibility with the TAC haplotype (p < 0.001) were observed. Also, lower RBC GLO1 activity was associated with the TAT haplotype (p = 0.002). CONCLUSIONS The rs1049346 of the GLO1 gene may be associated with ACS risk in South Indian T2DM patients, and the T and C allele might be essential precipitating and protective factors, respectively.
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Affiliation(s)
- Sushmita Bora
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| | - Prashant Shankarrao Adole
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India.
| | - Kolar Vishwanath Vinod
- Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| | - Ajith Ananthakrishna Pillai
- Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| | - Shaheer Ahmed
- Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
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Senavirathna L, Pan S, Chen R. Protein Advanced Glycation End Products and Their Implications in Pancreatic Cancer. Cancer Prev Res (Phila) 2023; 16:601-610. [PMID: 37578815 PMCID: PMC10843555 DOI: 10.1158/1940-6207.capr-23-0162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/14/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
Protein advanced glycation end products (AGE) formed by nonenzymatic glycation can disrupt the normal structure and function of proteins, and stimulate the receptor for AGEs (RAGE), triggering intricate mechanisms that are etiologically related to various chronic diseases, including pancreatic cancer. Many common risk factors of pancreatic cancer are the major sources for the formation of protein AGEs and glycative stress in the human body. Abnormal accumulation of protein AGEs can impair the cellular proteome and promote AGE-RAGE driven pro-inflammatory signaling cascades, leading to increased oxidative stress, protease resistance, protein dysregulation, transcription activity of STAT, NF-κB, and AP-1, aberrant status in ubiquitin-proteasome system and autophagy, as well as other molecular events that are susceptible for the carcinogenic transformation towards the development of neoplasms. Here, we review studies to highlight our understanding in the orchestrated molecular events in bridging the impaired proteome, dysregulated functional networks, and cancer hallmarks initiated upon protein AGE formation and accumulation in pancreatic cancer.
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Affiliation(s)
- Lakmini Senavirathna
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ru Chen
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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Dong L, Li Y, Chen Q, Liu Y, Qiao Z, Sang S, Zhang J, Zhan S, Wu Z, Liu L. Research advances of advanced glycation end products in milk and dairy products: Formation, determination, control strategy and immunometabolism via gut microbiota. Food Chem 2023; 417:135861. [PMID: 36906946 DOI: 10.1016/j.foodchem.2023.135861] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/22/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Advanced glycosylation end products (AGEs) are a series of complex compounds which generate in the advanced phase of Maillard reaction, which can pose a non-negligible risk to human health. This article systematically encompasses AGEs in milk and dairy products under different processing conditions, influencing factors, inhibition mechanism and levels among the different categories of dairy products. In particular, it describes the effects of various sterilization techniques on the Maillard reaction. Different processing techniques have a significant effect on AGEs content. In addition, it clearly articulates the determination methods of AGEs and even discusses its immunometabolism via gut microbiota. It is observed that the metabolism of AGEs can affect the composition of the gut microbiota, which further has an impact on intestinal function and the gut-brain axis. This research also provides a suggestion for AGEs mitigation strategies, which are beneficial to optimize the dairy production, especially innovative processing technology application.
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Affiliation(s)
- Lezhen Dong
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Ying Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Qin Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Yahui Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Zhaohui Qiao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Shangyuan Sang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Jingshun Zhang
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China
| | - Shengnan Zhan
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Zufang Wu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Lianliang Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, Zhejiang-Malaysia Joint Research Laboratory for Agricultural Product Processing and Nutrition School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China.
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11
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GRP75 Modulates Endoplasmic Reticulum-Mitochondria Coupling and Accelerates Ca 2+-Dependent Endothelial Cell Apoptosis in Diabetic Retinopathy. Biomolecules 2022; 12:biom12121778. [PMID: 36551205 PMCID: PMC9776029 DOI: 10.3390/biom12121778] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/11/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Endoplasmic reticulum (ER) and mitochondrial dysfunction play fundamental roles in the pathogenesis of diabetic retinopathy (DR). However, the interrelationship between the ER and mitochondria are poorly understood in DR. Here, we established high glucose (HG) or advanced glycosylation end products (AGE)-induced human retinal vascular endothelial cell (RMEC) models in vitro, as well as a streptozotocin (STZ)-induced DR rat model in vivo. Our data demonstrated that there was increased ER-mitochondria coupling in the RMECs, which was accompanied by elevated mitochondrial calcium ions (Ca2+) and mitochondrial dysfunction under HG or AGE incubation. Mechanistically, ER-mitochondria coupling was increased through activation of the IP3R1-GRP75-VDAC1 axis, which transferred Ca2+ from the ER to the mitochondria. Elevated mitochondrial Ca2+ led to an increase in mitochondrial ROS and a decline in mitochondrial membrane potential. These events resulted in the elevation of mitochondrial permeability and induced the release of cytochrome c from the mitochondria into the cytoplasm, which further activated caspase-3 and promoted apoptosis. The above phenomenon was also observed in tunicamycin (TUN, ER stress inducer)-treated cells. Meanwhile, BAPTA-AM (calcium chelator) rescued mitochondrial dysfunction and apoptosis in DR, which further confirmed of our suspicions. In addition, 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, was shown to reverse retinal dysfunction in STZ-induced DR rats in vivo. Taken together, our findings demonstrated that DR fueled the formation of ER-mitochondria coupling via the IP3R1-GRP75-VDAC1 axis and accelerated Ca2+-dependent cell apoptosis. Our results demonstrated that inhibition of ER-mitochondrial coupling, including inhibition of GRP75 or Ca2+ overload, may be a potential therapeutic target in DR.
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Abstract
The glyoxalase gene family consists of six structurally and functionally diverse enzymes with broad roles in metabolism. The common feature that defines this family is based on structural motifs that coordinate divalent cations which are required for activity. These family members have been implicated in a variety of physiological processes, including amino-acid metabolism (4-hydroxyphenylpyruvate dioxygenase; HPD), primary metabolism (methylmalonyl-CoA epimerase; MCEE), and aldehyde detoxication (glyoxalase 1; GLO1) and therefore have significant associations with disease. A central function of this family is the detoxification of reactive dicarbonyls (e.g., methylglyoxal), which react with cellular nucleophiles, resulting in the modification of lipids, proteins, and DNA. These damaging modifications activate canonical stress responses such as heat shock, unfolded protein, antioxidant, and DNA damage responses. Thus, glyoxalases serve an important role in homeostasis, preventing the pathogenesis of metabolic disease states, including obesity, diabetes, cardiovascular disease, renal failure, and aging. This review presents a thorough overview of the literature surrounding this diverse enzyme class. Although extensive literature exists for some members of this family (e.g., GLO1), little is known about the physiological role of glyoxalase domain-containing protein 4 (GLOD4) and 5 (GLOD5), paving the way for exciting avenues for future research.
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Affiliation(s)
- Dominique O Farrera
- Department of Pharmacology and College of Pharmacy, University of Arizona, Tucson, Arizona85721, United States
| | - James J Galligan
- Department of Pharmacology and College of Pharmacy, University of Arizona, Tucson, Arizona85721, United States
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13
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Koda Y. Unnatural biopolymers of saccharides and proteins conjugated with poly(2-oxazoline) and methacrylate-based polymers: from polymer design to bioapplication. Polym J 2022. [DOI: 10.1038/s41428-022-00695-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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14
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Svikle Z, Peterfelde B, Sjakste N, Baumane K, Verkauskiene R, Jeng CJ, Sokolovska J. Ubiquitin-proteasome system in diabetic retinopathy. PeerJ 2022; 10:e13715. [PMID: 35873915 PMCID: PMC9306563 DOI: 10.7717/peerj.13715] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 06/21/2022] [Indexed: 01/22/2023] Open
Abstract
Diabetic retinopathy (DR) is the most common complication of diabetes, being the most prevalent reason for blindness among the working-age population in the developed world. Despite constant improvement of understanding of the pathogenesis of DR, identification of novel biomarkers of DR is needed for improvement of patient risk stratification and development of novel prevention and therapeutic approaches. The ubiquitin-proteasome system (UPS) is the primary protein quality control system responsible for recognizing and degrading of damaged proteins. This review aims to summarize literature data on modifications of UPS in diabetes and DR. First, we briefly review the structure and functions of UPS in physiological conditions. We then describe how UPS is involved in the development and progression of diabetes and touch upon the association of UPS genetic factors with diabetes and its complications. Further, we focused on the effect of diabetes-induced hyperglycemia, oxidative stress and hypoxia on UPS functioning, with examples of studies on DR. In other sections, we discussed the association of several other mechanisms of DR (endoplasmic reticulum stress, neurodegeneration etc) with UPS modifications. Finally, UPS-affecting drugs and remedies are reviewed. This review highlights UPS as a promising target for the development of therapies for DR prevention and treatment and identifies gaps in existing knowledge and possible future study directions.
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Affiliation(s)
- Zane Svikle
- Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Beate Peterfelde
- Faculty of Medicine, University of Latvia, Riga, Latvia,Ophthalmology Department, Riga East University Hospital, Riga, Latvia
| | | | - Kristine Baumane
- Faculty of Medicine, University of Latvia, Riga, Latvia,Ophthalmology Department, Riga East University Hospital, Riga, Latvia
| | - Rasa Verkauskiene
- Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Chi-Juei Jeng
- Ophthalmology Department, Taipei Medical University Shuang Ho Hospital, Ministry of Health and Welfare, Taipei, The Republic of China (Taiwan),College of Medicine, Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
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15
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Wang Y, Cheng L, Zhao H, Li Z, Chen J, Cen Y, Zhang Z. The Therapeutic Role of ADSC-EVs in Skin Regeneration. Front Med (Lausanne) 2022; 9:858824. [PMID: 35755023 PMCID: PMC9218955 DOI: 10.3389/fmed.2022.858824] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/20/2022] [Indexed: 02/05/2023] Open
Abstract
Large skin defects caused by burns, unhealing chronic wounds, and trauma, are still an intractable problem for clinicians and researchers. Ideal skin regeneration includes several intricate and dynamic stages of wound repair and regeneration of skin physiological function. Adipose-derived stem cells (ADSCs), a type of mesenchymal stem cells (MSCs) with abundant resources and micro-invasive extraction protocols, have been reported to participate in each stage of promoting skin regeneration via paracrine effects. As essential products secreted by ADSCs, extracellular vesicles (EVs) derived from ADSCs (ADSC-EVs) inherit such therapeutic potential. However, ADSC-EVs showed much more clinical superiorities than parental cells. ADSC-EVs carry various mRNAs, non-coding RNAs, proteins, and lipids to regulate the activities of recipient cells and eventually accelerate skin regeneration. The beneficial role of ADSCs in wound repair has been widely accepted, while a deep comprehension of the mechanisms of ADSC-EVs in skin regeneration remains unclear. In this review, we provided a basic profile of ADSC-EVs. Moreover, we summarized the latest mechanisms of ADSC-EVs on skin regeneration from the aspects of inflammation, angiogenesis, cell proliferation, extracellular matrix (ECM) remodeling, autophagy, and oxidative stress. Hair follicle regeneration and skin barrier repair stimulated by ADSC-EVs were also reviewed. The challenges and prospects of ADSC-EVs-based therapies were discussed at the end of this review.
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Affiliation(s)
- Yixi Wang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Lihui Cheng
- Department of Central Sterile Supply, West China Hospital, Sichuan University, Chengdu, China
| | - Hanxing Zhao
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhengyong Li
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Junjie Chen
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ying Cen
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenyu Zhang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
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Gómez O, Perini-Villanueva G, Yuste A, Rodríguez-Navarro JA, Poch E, Bejarano E. Autophagy and Glycative Stress: A Bittersweet Relationship in Neurodegeneration. Front Cell Dev Biol 2022; 9:790479. [PMID: 35004686 PMCID: PMC8733682 DOI: 10.3389/fcell.2021.790479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/06/2021] [Indexed: 12/27/2022] Open
Abstract
Autophagy is a fine-tuned proteolytic pathway that moves dysfunctional/aged cellular components into the lysosomal compartment for degradation. Over the last 3 decades, global research has provided evidence for the protective role of autophagy in different brain cell components. Autophagic capacities decline with age, which contributes to the accumulation of obsolete/damaged organelles and proteins and, ultimately, leads to cellular aging in brain tissues. It is thus well-accepted that autophagy plays an essential role in brain homeostasis, and malfunction of this catabolic system is associated with major neurodegenerative disorders. Autophagy function can be modulated by different types of stress, including glycative stress. Glycative stress is defined as a cellular status with abnormal and accelerated accumulation of advanced glycation end products (AGEs). It occurs in hyperglycemic states, both through the consumption of high-sugar diets or under metabolic conditions such as diabetes. In recent years, glycative stress has gained attention for its adverse impact on brain pathology. This is because glycative stress stimulates insoluble, proteinaceous aggregation that is linked to the malfunction of different neuropathological proteins. Despite the emergence of new literature suggesting that autophagy plays a major role in fighting glycation-derived damage by removing cytosolic AGEs, excessive glycative stress might also negatively impact autophagic function. In this mini-review, we provide insight on the status of present knowledge regarding the role of autophagy in brain physiology and pathophysiology, with an emphasis on the cytoprotective role of autophagic function to ameliorate the adverse effects of glycation-derived damage in neurons, glia, and neuron-glia interactions.
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Affiliation(s)
- Olga Gómez
- School of Health Sciences and Veterinary School, Universidad CEU Cardenal Herrera, CEU Universities, Valencia, Spain
| | - Giuliana Perini-Villanueva
- Laboratory for Nutrition and Vision Research, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, United States
| | - Andrea Yuste
- School of Health Sciences and Veterinary School, Universidad CEU Cardenal Herrera, CEU Universities, Valencia, Spain
| | | | - Enric Poch
- School of Health Sciences and Veterinary School, Universidad CEU Cardenal Herrera, CEU Universities, Valencia, Spain
| | - Eloy Bejarano
- School of Health Sciences and Veterinary School, Universidad CEU Cardenal Herrera, CEU Universities, Valencia, Spain
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Rodríguez ML, Millán I, Ortega ÁL. Cellular targets in diabetic retinopathy therapy. World J Diabetes 2021; 12:1442-1462. [PMID: 34630899 PMCID: PMC8472497 DOI: 10.4239/wjd.v12.i9.1442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/08/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.
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Affiliation(s)
- María Lucía Rodríguez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
| | - Iván Millán
- Neonatal Research Group, Health Research Institute La Fe, Valencia 46026, Valencia, Spain
| | - Ángel Luis Ortega
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
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18
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The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy. Cells 2021; 10:cells10081852. [PMID: 34440621 PMCID: PMC8393707 DOI: 10.3390/cells10081852] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/09/2021] [Accepted: 07/15/2021] [Indexed: 12/19/2022] Open
Abstract
The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system.
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19
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Liu Q, Wang X, Yan H. Effect of thioltransferase on oxidative stress induced by high glucose and advanced glycation end products in human lens epithelial cells. Int J Ophthalmol 2021; 14:965-972. [PMID: 34282379 DOI: 10.18240/ijo.2021.07.02] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 04/08/2021] [Indexed: 12/30/2022] Open
Abstract
AIM To study the effect of thioltransferase (TTase) on oxidative stress in human lens epithelial cells (HLECs) induced by high glucose and advanced glycation end products (AGEs). METHODS HLECs were treated with 35.5 mmol/L glucose or 1.5 mg/mL AGEs modified bovine serum albumin (AGEs-BSA) as the experimental groups, respectively. Cells were collected at the time point of 1, 2, 3, and 4d. The TTase activity were measured accordingly. TTase mRNA levels were detected by quantitative reverse transcription polymerase chain response (qRT-RCR) and its protein level was detected by Western blot. The siRNA was used to knock down the expression of TTase. The activity of catalase (CAT) and superoxide dismutase (SOD), the content of reactive oxygen species (ROS) and the ratio of oxidized glutathione/total glutathione (GSSG/T-GSH) were assessed in different groups, respectively. RESULTS The level of TTase mRNA gradually increased and reached the top at 2d, then it decreased to the normal level at 4d, and the TTase activity increased from 2 to 3d in both high glucose and AGEs-BSA groups. The TTase expression elevated from 2d in high glucose group, and it began to rise from 3d in AGEs-BSA group. The activity of CAT and SOD showed a decrease and the content of ROS and the ratio of GSSG/T-GSH showed an increase in high glucose and AGEs-BSA group. These biochemical alterations were more prominent in the groups with TTase siRNA. CONCLUSION High glucose and AGEs can increase ROS content in HLECs; therefore, it induces oxidative stress. This may result in the decreased GSH and increased GSSG content, impaired activity of SOD and CAT. The up-regulated TTase likely provides oxidation damage repair induced by high glucose and AGEs in the early stage.
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Affiliation(s)
- Qing Liu
- Xi'an People's Hospital (Xi'an Fourth Hospital), Shaanxi Eye Hospital, Affiliated Guangren Hospital School of Medicine, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.,Department of Ophthalmology, No.986 Hospital of Air Force, PLA, Air Force Medical University, Xi'an 710054, Shaanxi Province, China
| | - Xu Wang
- Department of Ophthalmology, Xi'an Hong Hui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Hong Yan
- Xi'an People's Hospital (Xi'an Fourth Hospital), Shaanxi Eye Hospital, Affiliated Guangren Hospital School of Medicine, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.,Department of Ophthalmology, Tangdu Hospital, Air Force Medical University, Xi'an 710038, Shaanxi Province, China
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20
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Li X, Lv J, Li J, Ren X. Kir4.1 may represent a novel therapeutic target for diabetic retinopathy (Review). Exp Ther Med 2021; 22:1021. [PMID: 34373707 PMCID: PMC8343704 DOI: 10.3892/etm.2021.10453] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/28/2021] [Indexed: 12/27/2022] Open
Abstract
As the major cause of irreversible loss of vision in adults, diabetic retinopathy (DR) is one of the most serious complications of diabetes. The imbalance of the retinal microenvironment and destruction of the blood-retinal barrier have a significant role in the progression of DR. Inward rectifying potassium channel 4.1 (Kir4.1) is located on Müller cells and is closely related to potassium homeostasis, water balance and glutamate clearance in the whole retina. The present review discusses the functions of Kir4.1 in regulating the retinal microenvironment and related biological mechanisms in DR. In the future, Kir4.1 may represent a novel alternative therapeutic target for DR through affecting the retinal microenvironment.
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Affiliation(s)
- Xiaoyu Li
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Department of Radiotherapy Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Jiajun Lv
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Department of Radiotherapy Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Jiazhi Li
- Department of Radiotherapy Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Xiang Ren
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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21
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Fujii J, Homma T, Miyata S, Takahashi M. Pleiotropic Actions of Aldehyde Reductase (AKR1A). Metabolites 2021; 11:343. [PMID: 34073440 PMCID: PMC8227408 DOI: 10.3390/metabo11060343] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
We provide an overview of the physiological roles of aldehyde reductase (AKR1A) and also discuss the functions of aldose reductase (AKR1B) and other family members when necessary. Many types of aldehyde compounds are cytotoxic and some are even carcinogenic. Such toxic aldehydes are detoxified via the action of AKR in an NADPH-dependent manner and the resulting products may exert anti-diabetic and anti-tumorigenic activity. AKR1A is capable of reducing 3-deoxyglucosone and methylglyoxal, which are reactive intermediates that are involved in glycation, a non-enzymatic glycosylation reaction. Accordingly, AKR1A is thought to suppress the formation of advanced glycation end products (AGEs) and prevent diabetic complications. AKR1A and, in part, AKR1B are responsible for the conversion of d-glucuronate to l-gulonate which constitutes a process for ascorbate (vitamin C) synthesis in competent animals. AKR1A is also involved in the reduction of S-nitrosylated glutathione and coenzyme A and thereby suppresses the protein S-nitrosylation that occurs under conditions in which the production of nitric oxide is stimulated. As the physiological functions of AKR1A are currently not completely understood, the genetic modification of Akr1a could reveal the latent functions of AKR1A and differentiate it from other family members.
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Affiliation(s)
- Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan;
| | - Takujiro Homma
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan;
| | - Satoshi Miyata
- Miyata Diabetes and Metabolism Clinic, 5-17-21 Fukushima, Fukushima-ku, Osaka 553-0003, Japan;
| | - Motoko Takahashi
- Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan;
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22
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Lee DY, Lin YC, Chang GD. Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling. Antioxidants (Basel) 2021; 10:antiox10020326. [PMID: 33671767 PMCID: PMC7926409 DOI: 10.3390/antiox10020326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 11/18/2022] Open
Abstract
Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into nontoxic metabolites. Converting MG-glutathione hemithioacetal to S-d-lactoylglutathione by GlxI is the rate-determining step of the enzyme system. In this study, we found lactic acid accumulated during insulin stimulation in cells, however, cellular MG and S-d-lactoylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently removed by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic 13C3-MG, the flux of MG from extracellular and intracellular origins was dissected. While insulin induced an influx of extracellular MG, metformin inhibited the trafficking of MG across the plasma membrane. Therefore, metformin could maintain the extracellular MG by means of reducing the secretion of MG rather than facilitating the scavenging. In addition, metformin may affect the glyoxalase system by controlling the cellular redox state through replenishing reduced glutathione. Overall, alternative biochemical regulation of the glyoxalase system mediated by insulin signaling or molecules like biguanides may control cellular MG homeostasis.
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Affiliation(s)
- Der-Yen Lee
- Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- Correspondence: (D.-Y.L.); (G.-D.C.); Tel.: +886-4-22053366#3505 (D.-Y.L.); +886-2-33664071 (G.-D.C.); Fax: +886-2-22037690 (D.-Y.L.); +886-2-23635038 (G.-D.C.)
| | - Yu-Chin Lin
- Ph.D. Program for Health Science and Industry, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan;
| | - Geen-Dong Chang
- Graduate Institute of Biochemical Sciences, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 106, Taiwan
- Correspondence: (D.-Y.L.); (G.-D.C.); Tel.: +886-4-22053366#3505 (D.-Y.L.); +886-2-33664071 (G.-D.C.); Fax: +886-2-22037690 (D.-Y.L.); +886-2-23635038 (G.-D.C.)
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Fan Gaskin JC, Shah MH, Chan EC. Oxidative Stress and the Role of NADPH Oxidase in Glaucoma. Antioxidants (Basel) 2021; 10:antiox10020238. [PMID: 33557289 PMCID: PMC7914994 DOI: 10.3390/antiox10020238] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 02/08/2023] Open
Abstract
Glaucoma is characterised by loss of retinal ganglion cells, and their axons and many pathophysiological processes are postulated to be involved. It is increasingly understood that not one pathway underlies glaucoma aetiology, but rather they occur as a continuum that ultimately results in the apoptosis of retinal ganglion cells. Oxidative stress is recognised as an important mechanism of cell death in many neurodegenerative diseases, including glaucoma. NADPH oxidase (NOX) are enzymes that are widely expressed in vascular and non-vascular cells, and they are unique in that they primarily produce reactive oxygen species (ROS). There is mounting evidence that NOX are an important source of ROS and oxidative stress in glaucoma and other retinal diseases. This review aims to provide a perspective on the complex role of oxidative stress in glaucoma, in particular how NOX expression may influence glaucoma pathogenesis as illustrated by different experimental models of glaucoma and highlights potential therapeutic targets that may offer a novel treatment option to glaucoma patients.
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Affiliation(s)
- Jennifer C Fan Gaskin
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne 3002, Australia
| | - Manisha H Shah
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne 3002, Australia
| | - Elsa C Chan
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne 3002, Australia
- Department of Medicine, University of Melbourne, Parkville 3010, Australia
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Oxidative Stress in Diabetic Retinopathy. Antioxidants (Basel) 2021; 10:antiox10010050. [PMID: 33406579 PMCID: PMC7823526 DOI: 10.3390/antiox10010050] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 12/31/2020] [Indexed: 02/08/2023] Open
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Ananth S, Miyauchi S, Thangaraju M, Jadeja RN, Bartoli M, Ganapathy V, Martin PM. Selenomethionine (Se-Met) Induces the Cystine/Glutamate Exchanger SLC7A11 in Cultured Human Retinal Pigment Epithelial (RPE) Cells: Implications for Antioxidant Therapy in Aging Retina. Antioxidants (Basel) 2020; 10:antiox10010009. [PMID: 33374239 PMCID: PMC7823377 DOI: 10.3390/antiox10010009] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Oxidative damage has been identified as a major causative factor in degenerative diseases of the retina; retinal pigment epithelial (RPE) cells are at high risk. Hence, identifying novel strategies for increasing the antioxidant capacity of RPE cells, the purpose of this study, is important. Specifically, we evaluated the influence of selenium in the form of selenomethionine (Se-Met) in cultured RPE cells on system xc- expression and functional activity and on cellular levels of glutathione, a major cellular antioxidant. ARPE-19 and mouse RPE cells were cultured with and without selenomethionine (Se-Met), the principal form of selenium in the diet. Promoter activity assay, uptake assay, RT-PCR, northern and western blots, and immunofluorescence were used to analyze the expression of xc-, Nrf2, and its target genes. Se-Met activated Nrf2 and induced the expression and function of xc- in RPE. Other target genes of Nrf2 were also induced. System xc- consists of two subunits, and Se-Met induced the subunit responsible for transport activity (SLC7A11). Selenocysteine also induced xc- but with less potency. The effect of Se-met on xc- was associated with an increase in maximal velocity and an increase in substrate affinity. Se-Met increased the cellular levels of glutathione in the control, an oxidatively stressed RPE. The Se-Met effect was selective; under identical conditions, taurine transport was not affected and Na+-coupled glutamate transport was inhibited. This study demonstrates that Se-Met enhances the antioxidant capacity of RPE by inducing the transporter xc- with a consequent increase in glutathione.
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Affiliation(s)
- Sudha Ananth
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
| | - Seiji Miyauchi
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
| | - Ravirajsinh N. Jadeja
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
- Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA;
| | - Manuela Bartoli
- Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech Health Science Center, Lubbock, TX 79430, USA;
| | - Pamela M. Martin
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
- Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Correspondence: ; Tel.: +706-721-4220; Fax: +706-721-6608
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