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Esmaeilkhanian H, Gutierrez KG, Myung D, Fisher AC. Detection Rate of Diabetic Retinopathy Before and After Implementation of Autonomous AI-based Fundus Photograph Analysis in a Resource-Limited Area in Belize. Clin Ophthalmol 2025; 19:993-1006. [PMID: 40144136 PMCID: PMC11937645 DOI: 10.2147/opth.s490473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/13/2025] [Indexed: 03/28/2025] Open
Abstract
Purpose To evaluate the use of an autonomous artificial intelligence (AI)-based device to screen for diabetic retinopathy (DR) and to evaluate the frequency of diabetes mellitus (DM) and DR in an under-resourced population served by the Stanford Belize Vision Clinic (SBVC). Patients and Methods The records of all patients from 2017 to 2024 were collected and analyzed, dividing the study into two time periods: Pre-AI (before June 2022, prior to the implementation of the LumineticsCore® device at SBVC) and Post-AI (from June 2022 to the present) and subdivided into post-COVID19 and pre-COVID19 periods. Patients were categorized based on self-reported past medical history (PMH) as DM positive (diagnosed DM) and DM negative (no PMH of DM). AI camera outcomes included: negative for more than mild DR (MTMDR), positive for MTMDR, and insufficient exam quality. Results A total of 1897 patients with a mean age of 47.6 years were included. The gradability of encounters by the AI device was 89.1%. The frequency of DR detection increased significantly in the Post-AI period (55/639) compared to the Pre-AI period (38/1258), including during the COVID-19 pandemic. The mean age of DR diagnosis was significantly lower in the Post-AI period (44.1 years) compared to Pre-AI period (60.7 years) among DM negative patients. There was a significant association between having DR and hypertension. Additionally, the detection rate of DM increased in the Post-AI period compared to Pre-AI period. Conclusion Autonomous AI-based screening significantly improves the detection of patients with DR in areas with limited healthcare resources by reducing dependence on on-field ophthalmologists. This innovative approach can be seamlessly integrated into primary care settings, with technicians capturing images quickly and efficiently within just a few minutes. This study demonstrates the effectiveness of autonomous AI in identifying patients with both DR and DM, as well as associated high-burden diseases such as hypertension, across various age ranges.
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Affiliation(s)
- Houri Esmaeilkhanian
- Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Karen G Gutierrez
- Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - David Myung
- Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Ann Caroline Fisher
- Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
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Xu J, Shen R, Qian M, Ning L, Zhang X, Xie B, Jiang Y, Zhou Z, Dong W. Obtusin ameliorates diabetic retinopathy by inhibiting oxidative stress and inflammation. Psychopharmacology (Berl) 2024; 241:2471-2484. [PMID: 39488807 DOI: 10.1007/s00213-024-06689-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 09/11/2024] [Indexed: 11/04/2024]
Abstract
RATIONALE Diabetic retinopathy (DR) is linked to an increased risk of psychiatric and neurological conditions, largely due to chronic inflammation, oxidative stress, and microvascular damage associated with the disease. Emerging evidence suggests that Cassia seed extract has significant anti-inflammatory and antioxidant properties. However, the therapeutic potential of obtusin, a major compound in Cassia seed, and its underlying mechanisms remain unclear. OBJECTIVE This study aimed to evaluate the therapeutic efficacy of obtusin in the treatment of DR. METHODS Db/db mice were treated with obtusin (5 and 10 mg/kg/day) for 12 weeks. Throughout the study, body weight, blood glucose levels, and lipid profiles were monitored. Retinal histopathology and transmission electron microscopy were used to assess the pharmacological effects of obtusin in vivo. Additionally, in vitro assays were conducted on human retinal microvascular endothelial cells cultured under high glucose conditions to explore obtusin's potential role in mitigating DR. RESULTS Obtusin treatment in diabetic mice significantly reduced blood glucose levels, improved dyslipidemia, thickened retinal layers, reduced retinal oxidative stress, and inhibited the upregulation of inflammatory cytokines. It also lessened fundus microangiopathy and preserved the retina's normal barrier function. Mechanistic in vitro analysis suggested that obtusin targets the Poldip2-Nox4 oxidative stress axis and the NF-κB-MAPK-VEGFA inflammatory pathway, both of which are implicated in DR. CONCLUSIONS Our findings suggest that the Poldip2-Nox4 oxidative stress axis and the NF-κB-MAPK-VEGFA inflammatory pathway could be therapeutic targets for obtusin in the treatment of DR and its associated psychiatric and neurological conditions.
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Affiliation(s)
- Jingyi Xu
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Rongjing Shen
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Mengting Qian
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Luying Ning
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Xinyu Zhang
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Bingqing Xie
- Laboratory of Neurological Diseases and Brain Function, Institute of Epigenetics and Brain Science, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Yong Jiang
- Laboratory of Neurological Diseases and Brain Function, Institute of Epigenetics and Brain Science, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Zhengjun Zhou
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People's Republic of China.
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People's Republic of China.
| | - Wei Dong
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People's Republic of China.
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Kumar J, Malaviya P, Kowluru RA. Long noncoding RNAs and metabolic memory associated with continued progression of diabetic retinopathy. J Diabetes 2024; 16:e70009. [PMID: 39558680 PMCID: PMC11574110 DOI: 10.1111/1753-0407.70009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/11/2024] [Accepted: 08/25/2024] [Indexed: 11/20/2024] Open
Abstract
Progression of diabetic retinopathy resists arrest even after institution of intensive glycemic control, suggesting a "metabolic memory" phenomenon, but the mechanism responsible for this phenomenon is still elusive. Gene expression and biological processes can also be regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame for translation, and several LncRNAs are aberrantly expressed in diabetes. Our aim was to identify retinal LncRNAs that fail to reverse after termination of hyperglycemia. Microarray analysis was performed on retinal RNA from streptozotocin-induced diabetic rats in poor glycemic control for 8 months, followed by in good glycemic control (blood glucose >400 mg/dL), or for 4 months, with four additional months of good glycemic control (blood glucose <150 mg/dL). Differentially expressed LncRNAs and mRNAs were identified through Volcano filtering, and their functions were predicted using gene ontology and pathway enrichment analyses. Compared with age-matched normal rats, rats in continuous poor glycemic control had >1479 differentially expressed LncRNAs (710 downregulated, 769 upregulated), and among those, 511 common LncRNAs had similar expression in Diab and Rev groups (139 downregulated, 372 upregulated). Gene Ontology/pathway analysis identified limited LncRNAs in biological processes, but analysis based on biological processes/molecular function revealed >350 genes with similar expression in Diab and Rev groups; these genes were mainly associated with stress response, cell death, mitochondrial damage and cytokine production. Thus, identifying retinal LncRNAs and their gene targets that do not benefit from termination of hyperglycemia have potential to serve as therapeutic targets to slow down the progression of diabetic retinopathy.
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Affiliation(s)
- Jay Kumar
- Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, USA
| | - Pooja Malaviya
- Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, USA
| | - Renu A Kowluru
- Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, USA
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Kato Y, Ariyoshi K, Nohara Y, Matsunaga N, Shimauchi T, Shindo N, Nishimura A, Mi X, Kim SG, Ide T, Kawanishi E, Ojida A, Nakashima N, Mori Y, Nishida M. Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism. Br J Pharmacol 2024; 181:4328-4347. [PMID: 38986570 DOI: 10.1111/bph.16487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 05/05/2024] [Accepted: 05/18/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND AND PURPOSE Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models. EXPERIMENTAL APPROACH Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD). KEY RESULTS In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose. CONCLUSION AND IMPLICATIONS Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.
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Affiliation(s)
- Yuri Kato
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Ariyoshi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasunobu Nohara
- Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan
| | - Naoya Matsunaga
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Tsukasa Shimauchi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
- Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
| | - Naoya Shindo
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akiyuki Nishimura
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Xinya Mi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Sang Geon Kim
- College of Pharmacy, Dongguk University-Seoul, Goyang-si, South Korea
| | - Tomomi Ide
- Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Kawanishi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akio Ojida
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Nakashima
- Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuo Mori
- Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Motohiro Nishida
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
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Jawharji MT, Alshammari GM, Binobead MA, Albanyan NM, Al-Harbi LN, Yahya MA. Comparative Efficacy of Low-Carbohydrate and Ketogenic Diets on Diabetic Retinopathy and Oxidative Stress in High-Fat Diet-Induced Diabetic Rats. Nutrients 2024; 16:3074. [PMID: 39339674 PMCID: PMC11435414 DOI: 10.3390/nu16183074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
This study examined the effect of a low-carbohydrate diet (LCD) and a low-carbohydrate ketogenic diet (LCKD) on diabetic retinopathy in high-fat diet-induced diabetes mellitus in rats and studied the mechanisms of action. Rats were divided into four groups: the Control group, which was fed a normal diet for 16 weeks; the HFD group, which was fed a high-fat diet (HFD) for the first 8 weeks and then switched to a normal diet for 8 weeks; the HFD+LCD group, fed a HFD for 8 weeks followed by an LCD for 8 weeks, and the HFD+LCKD group, which was fed a HFD for 8 weeks followed by an LCKD for 8 more weeks. Both the LCD and the LCKD effectively reduced the final body and total fat weights and decreased fasting serum levels of glucose, insulin, hemoglobin A1 (HbA1C), triglycerides, cholesterol, and LDL-c. They also reduced the levels of malondialdehyde (MDA), tumor necrosis factor-α, vascular endothelial factor, caspapse-3, and bax. In the HFD rats, we found increased serum levels of β-Hydroxybutyrate and upregulated expression of Bcl2, glutathione, superoxide dismutase, and hemeoxygenase-1. Moreover, the LCD and LCKD significantly reduced mRNA levels of Kelch-like ECH-associated protein 1 (Keap1) and enhanced mRNA and nuclear concentrations of nuclear factor erythroid factor 2 (Nrf2). All these effects were associated with improved layers of the retina in the HFD - LCD and HFD + LCKD rats but not in HFD animals. The impact of the LCKD was always more profound on all measured parameters and on improving the structure of the retina compared to the LCD. In conclusion, the LCKD is superior to the LCD in preventing diabetic retinopathy in HFD-fed rats. Mechanistically, our results suggest that the hypoglycemic and hypolipidemic conditions and the Nrf2-dependent antioxidant and anti-inflammatory effects may be involved in the preventative effects of the LCD and LCKD.
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Affiliation(s)
- Monya T. Jawharji
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh 11451, Saudi Arabia; (M.T.J.); (M.A.B.); (L.N.A.-H.); (M.A.Y.)
| | - Ghedeir M. Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh 11451, Saudi Arabia; (M.T.J.); (M.A.B.); (L.N.A.-H.); (M.A.Y.)
| | - Manal Abdulaziz Binobead
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh 11451, Saudi Arabia; (M.T.J.); (M.A.B.); (L.N.A.-H.); (M.A.Y.)
| | - Nouf Mohammed Albanyan
- Department of Optometry, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Laila Naif Al-Harbi
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh 11451, Saudi Arabia; (M.T.J.); (M.A.B.); (L.N.A.-H.); (M.A.Y.)
| | - Mohammed Abdo Yahya
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh 11451, Saudi Arabia; (M.T.J.); (M.A.B.); (L.N.A.-H.); (M.A.Y.)
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Wang J, Zhang H. Prevalence of diabetic retinopathy and its risk factors in rural patients with type 2 diabetes referring to Beijing Huairou Hospital, China. BMC Ophthalmol 2024; 24:336. [PMID: 39128998 PMCID: PMC11318320 DOI: 10.1186/s12886-024-03606-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 08/01/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND China has the largest population of diabetic patients worldwide. A diverse population and regional discrepancy in access to health care and diabetes management may lead to unique risk factors for diabetic retinopathy (DR) in different regions of China. This study aimed to evaluate the prevalence and risk factors of DR in rural patients with type 2 diabetes. METHODS This hospital-based cross-sectional study recruited a sample of 704 type 2 diabetic patients from rural areas referred to Beijing Huairou Hospital, China, from June 1, 2022, to June 1, 2023. The medical history, demographic information, and results of laboratory examinations of patients were collected and analyzed. The diagnosis of DR were performed by experienced ophthalmologists using mydriatic fundus photography. RESULTS Out of all patients, 53.8% were male and 46.2% were female. The mean age of patients and duration of diabetes were 54.9 ± 13.0 and 6.2 ± 4.5 years, respectively. The DR prevalence was 16.8%. The independent risk factors for DR in multivariate analysis were diabetes duration > 10 years (OR = 9.16, 95%CI = 5.49-15.30), fasting plasma glucose ≥ 7.2 mmol/L (OR = 3.25, 95%CI = 1.42-7.42), glycosylated hemoglobin ≥ 7% (OR = 6.49, 95%CI = 2.59-16.23), hypertension (OR = 1.59, 95%CI = 1.05-2.40), hyperlipidemia (OR = 2.16, 95%CI = 1.30-3.59), diabetic nephropathy (OR = 1.95, 95%CI = 1.17-3.23), high uric acid level (OR = 3.57, 95%CI = 1.56-8.15), high albumin to creatinine ratio (OR = 2.48, 95%CI = 1.06-5.82), and insulin treatment (OR = 1.79, 95%CI = 1.12-2.88). CONCLUSIONS This study evaluated the DR prevalence and its associated risk factors among type 2 diabetic patients from rural areas in Beijing's Huairou District, China. Paying attention to these risk factors may be useful in screening high-risk diabetic patients for DR and adopting early preventive and therapeutic interventions.
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Affiliation(s)
- Jing Wang
- Department of Ophthalmology, Beijing Huairou Hospital, No.9, Yongtai North Road, Huairou District, Beijing, 101400, China.
| | - Haifeng Zhang
- Department of Ophthalmology, Beijing Huairou Hospital, No.9, Yongtai North Road, Huairou District, Beijing, 101400, China
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Augustine-Wofford K, Connaughton VP, McCarthy E. Are Hyperglycemia-Induced Changes in the Retina Associated with Diabetes-Correlated Changes in the Brain? A Review from Zebrafish and Rodent Type 2 Diabetes Models. BIOLOGY 2024; 13:477. [PMID: 39056672 PMCID: PMC11273949 DOI: 10.3390/biology13070477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/28/2024]
Abstract
Diabetes is prevalent worldwide, with >90% of the cases identified as Type 2 diabetes. High blood sugar (hyperglycemia) is the hallmark symptom of diabetes, with prolonged and uncontrolled levels contributing to subsequent complications. Animal models have been used to study these complications, which include retinopathy, nephropathy, and peripheral neuropathy. More recent studies have focused on cognitive behaviors due to the increased risk of dementia/cognitive deficits that are reported to occur in older Type 2 diabetic patients. In this review, we collate the data reported from specific animal models (i.e., mouse, rat, zebrafish) that have been examined for changes in both retina/vision (retinopathy) and brain/cognition, including db/db mice, Goto-Kakizaki rats, Zucker Diabetic Fatty rats, high-fat diet-fed rodents and zebrafish, and hyperglycemic zebrafish induced by glucose immersion. These models were selected because rodents are widely recognized as established models for studying diabetic complications, while zebrafish represent a newer model in this field. Our goal is to (1) summarize the published findings relevant to these models, (2) identify similarities in cellular mechanisms underlying the disease progression that occur in both tissues, and (3) address the hypothesis that hyperglycemic-induced changes in retina precede or predict later complications in brain.
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Affiliation(s)
| | - Victoria P. Connaughton
- Department of Biology, American University, Washington, DC 20016, USA; (K.A.-W.); (E.M.)
- Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
| | - Elizabeth McCarthy
- Department of Biology, American University, Washington, DC 20016, USA; (K.A.-W.); (E.M.)
- Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
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Alsabaani NA, Amawi K, Eleawa SM, Nabeel Ibrahim W, Aldhaban W, Alaraj AM, Alkhalaf B, Sami W, Alshaikhli H, Alkhateeb MA. Nrf-2-dependent antioxidant and anti-inflammatory effects underlie the protective effect of esculeoside A against retinal damage in streptozotocin-induced diabetic rats. Biomed Pharmacother 2024; 173:116461. [PMID: 38503237 DOI: 10.1016/j.biopha.2024.116461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024] Open
Abstract
Esculeoside A (ESA) is a tomato-derived glycoside with antioxidant and anti-inflammatory properties. The protective effect of ESA against diabetic retinopathy is not well-investigated and was the core objective of this study. In addition, we tested if such protection involves the activation of Nrf2 signaling. Type 1 diabetes mellitus (T1DM) was induced in adult Wistar male rats by an intraperitoneal injection of streptozotocin (65 mg/kg). Non-diabetic and T1DM rats were divided into two subgroup groups given either the vehicle or ESA (100 mg)/kg. An additional T1DM group was given ESA (100 mg/kg) and an Nrf2 inhibitor (2 mg/kg) (n=8 rats/group). Treatments continued for 12 weeks. In this study, according to the histological features, ESA improved the structure of ganglionic cells and increased the number of cells of the inner nuclear and plexiform layers in the retinas of T1DM rats. Concomitantly, it reduced the retina levels of malondialdehyde (lipid peroxides), vascular endothelial growth factor, interleukin-6, tumor necrosis factor-α, Bax, and caspase-3. In the retinas of the control and diabetic rats, ESA boosted the levels of total glutathione, superoxide dismutase, heme-oxygenase-1, and Bcl2, reduced the mRNA levels of REDD1, and enhanced cytoplasmic and nuclear levels of Nrf2. However, ESA failed to alter the mRNA levels of Nrf2 and keap1, protein levels of keap1, plasma glucose, plasma insulin, serum triglycerides, cholesterol, and LDL-c in both the control and T1DM rats. In conclusion, ESA alleviates retinopathy in T1DM rats by suppressing REDD1-associated degradation and inhibiting the Nrf2/antioxidant axis.
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Affiliation(s)
- Nasser A Alsabaani
- Department of Ophthalmology, College of Medicine, King Khalid University, Abha P.O.Box 61421, Saudi Arabia.
| | - Kawther Amawi
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Zarqa University, Al-Zarqa, P.O. Box: 132222, Jordan.
| | - Samy M Eleawa
- Department of Applied Medical Sciences. College of Health Sciences, Public Authority for Applied Education and Training (PAAET), Kuwait P.O. Box: 2378, Kuwait.
| | - Wisam Nabeel Ibrahim
- Department of Biomedical Sciences, College of Health Sciences, QU health, Qatar University, Doha, P.O. Box: 2713, Qatar.
| | - Walid Aldhaban
- Department of Ophthalmology, College of Medicine, King Khalid University, Abha P.O.Box 61421, Saudi Arabia.
| | - Ahmad Mohammad Alaraj
- Department of Ophthalmology, College of Medicine, Qassim University, Qassim P.O. Box 52751, Saudi Arabia.
| | - Badr Alkhalaf
- Department of Environmental Sciences. College of Health Health Sciences, PAAET, Kuwait.
| | - Waqas Sami
- Department of pre-clinical affairs, College of Nursing, QU health, Qatar University, Doha P.O. Box: 2713, Qatar.
| | - Hisham Alshaikhli
- Department of pre-clinical affairs, College of Nursing, QU health, Qatar University, Doha P.O. Box: 2713, Qatar.
| | - Mahmoud A Alkhateeb
- Department of pre-clinical affairs, College of Nursing, QU health, Qatar University, Doha P.O. Box: 2713, Qatar.
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Zhang Y, Jiao X, Liu J, Feng G, Luo X, Zhang M, Zhang B, Huang L, Long Q. A new direction in Chinese herbal medicine ameliorates for type 2 diabetes mellitus: Focus on the potential of mitochondrial respiratory chain complexes. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117484. [PMID: 38012971 DOI: 10.1016/j.jep.2023.117484] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetes is a common chronic disease. Chinese herbal medicine (CHM) has a history of several thousand years in the treatment of diabetes, and active components with hypoglycemic effects extracted from various CHM, such as polysaccharides, flavonoids, terpenes, and steroidal saponins, have been widely used in the treatment of diabetes. AIM OF THE STUDY Research exploring the potential of various CHM compounds to regulate the mitochondrial respiratory chain complex to improve type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS The literature data were primarily obtained from authoritative databases such as PubMed, CNKI, Wanfang, and others within the last decade. The main keywords used include "type 2 diabetes mellitus", "Chinese medicine", "Chinese herbal medicine", "mitochondrial respiratory chain complex", and "mitochondrial dysfunction". RESULTS Chinese herbal medicine primarily regulates the activity of mitochondrial respiratory chain complexes in various tissues such as liver, adipose tissue, skeletal muscle, pancreatic islets, and small intestine. It improves cellular energy metabolism through hypoglycemic, antioxidant, anti-inflammatory and lipid-modulating effects. Different components of CHM can regulate the same mitochondrial respiratory chain complexes, while the same components of a particular CHM can regulate different complex activities. The active components of CHM target different mitochondrial respiratory chain complexes, regulate their aberrant changes and effectively improve T2DM and its complications. CONCLUSION Chinese herbal medicine can modulate the function of mitochondrial respiratory chain complexes in various cell types and exert their hypoglycemic effects through various mechanisms. CHM has significant therapeutic potential in regulating mitochondrial respiratory chain complexes to improve T2DM, but further research is needed to explore the underlying mechanisms and conduct clinical trials to assess the safety and efficacy of these medications. This provides new perspectives and opportunities for personalized improvement and innovative developments in diabetes management.
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Affiliation(s)
- Yinghui Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xinyue Jiao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Jianying Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Gang Feng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xia Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Mingyue Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Binzhi Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Lizhen Huang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Qinqiang Long
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
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10
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Malaviya P, Kowluru RA. Homocysteine and mitochondrial quality control in diabetic retinopathy. EYE AND VISION (LONDON, ENGLAND) 2024; 11:5. [PMID: 38229140 PMCID: PMC10790378 DOI: 10.1186/s40662-023-00362-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/08/2023] [Indexed: 01/18/2024]
Abstract
BACKGROUND Diabetic retinopathy is a progressive disease, and one of the key metabolic abnormalities in the pathogenesis of diabetic retinopathy, mitochondrial damage, is also influenced by the duration of hyperglycemia. Mitochondrial quality control involves a coordination of mitochondrial dynamics, biogenesis and removal of the damaged mitochondria. In diabetes, these processes are impaired, and the damaged mitochondria continue to produce free radicals. Diabetic patients also have high homocysteine and reduced levels of hydrogen sulfide, and hyperhomocysteinemia is shown to exacerbate diabetes-induced mitochondrial damage and worsen their dynamics. This study aims to investigate the temporal relationship between hyperhomocysteinemia and retinal mitochondrial quality control in diabetic retinopathy. METHODS Human retinal endothelial cells incubated in 20 mM D-glucose for 24 to 96 h, in the absence or presence of 100 µM homocysteine, with/without a hydrogen sulfide donor GYY4137, were analyzed for mitochondrial ROS (MitoSox fluorescence), DNA damage (transcripts of mtDNA-encoded ND6 and CytB), copy numbers, oxygen consumption rate (Seahorse XF analyzer) and mitophagy (mitophagosomes immunofluorescence labeling and flow cytometry). Results were confirmed in the retina from mice genetically manipulated for hyperhomocysteinemia (cystathionine β-synthase deficient mice, Cbs+/-), streptozotocin-induced diabetic for 8 to 24 weeks. At 24 weeks of diabetes, vascular health was evaluated by counting acellular capillaries in the trypsin digested retinal vasculature and by fluorescein angiography. RESULTS Homocysteine, in high glucose medium, exacerbated mitochondrial ROS production, mtDNA damage and impaired mitochondrial respiration within 24 h, and slowed down/worsened mitochondrial biogenesis and mitophagy, as compared to 48 to 96 h in high glucose alone. GYY4137 supplementation ameliorated homocysteine + high glucose-induced mitochondrial damage and impairment in biogenesis and mitophagy. Similar results were obtained from Cbs+/- mice-mitochondrial ROS, mtDNA damage and decline in biogenesis and mitophagy were observed within eight weeks of diabetes vs. 16 to 24 weeks of diabetes in Cbs+/+ mice, and at 24 weeks of diabetes, Cbs+/- mice had significantly higher acellular capillaries and vascular leakage. CONCLUSIONS Hyperhomocysteinemia, in a hyperglycemic environment, overwhelms the mitochondria, accelerating and exacerbating their dysfunction, and also delays/worsens their removal, augmenting the development of diabetic retinopathy. Thus, our results strengthen the importance of maintaining homocysteine-hydrogen sulfide balance during the early stages of diabetes for a patient to prevent/retard vision loss.
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Affiliation(s)
- Pooja Malaviya
- Department of Ophthalmology, Visual Sciences and Anatomical Sciences, Wayne State University, 4717 St. Antoine, Detroit, MI, 48201, USA
| | - Renu A Kowluru
- Department of Ophthalmology, Visual Sciences and Anatomical Sciences, Wayne State University, 4717 St. Antoine, Detroit, MI, 48201, USA.
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11
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Kaur A, Kumar R, Sharma A. Diabetic Retinopathy Leading to Blindness- A Review. Curr Diabetes Rev 2024; 20:e240124225997. [PMID: 38275038 DOI: 10.2174/0115733998274599231109034741] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/28/2023] [Accepted: 10/18/2023] [Indexed: 01/27/2024]
Abstract
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes that damages the retina, leading to blindness. People with type 1 diabetes are at greater risk of developing DR than people with type 2 diabetes. Diabetic retinopathy may be divided into two primary categories: Proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR). There are multiple risk factors for the onset and progression of diabetic retinopathy, such as hypertension, obesity, smoking, duration of diabetes, and genetics. Numerous investigations have evaluated the levels of a wide range of inflammatory chemokines within DR patients' serum, vitreous, and aqueous fluids. In diabetic retinopathy, the vitreous fluid exhibited rises in angiogenic factors like platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) or declines in antiangiogenic factors like pigment epithelium-derived factor (PEDF). For prevention of diabetic retinopathy, more physical activity as well as less sedentary behavior were linked to a reduced likelihood of DR. Supplementing with nutraceuticals containing vitamins (B1, B2, B6, B12, C, D, E, and l-methyl folate) and mineral (zinc) can help decrease or avoid an outbreak of DR. Only laser photocoagulation and Anti-vascular endothelial growth factor (Anti-VEGF) injections are advised as favorable therapies in severe retinopathy. When it comes to treating DR's VEGF levels, inflammation, oxidative stress, apoptosis, and angiogenesis, Traditional Chinese medicine (TCM) has an excellent future.
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Affiliation(s)
- Amandeep Kaur
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, Punjab, India
| | - Ranjeet Kumar
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, Punjab, India
| | - Amit Sharma
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, Punjab, India
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12
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Xu YX, Pu SD, Zhang YT, Tong XW, Sun XT, Shan YY, Gao XY. Insulin resistance is associated with the presence and severity of retinopathy in patients with type 2 diabetes. Clin Exp Ophthalmol 2024; 52:63-77. [PMID: 38130181 DOI: 10.1111/ceo.14344] [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: 05/26/2023] [Revised: 10/15/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND To assess the relationship between novel insulin resistance (IR) indices and the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes. METHODS This is a cross-sectional study involving 2211 patients. The study outcomes were DR events. The study exposures were IR indices including estimated glucose disposal rate (eGDR), natural logarithm of glucose disposal rate (lnGDR), metabolic insulin resistance score (METS-IR), triglyceride glucose index-body mass index (TyG-BMI), triglyceride glucose index-waist-to-hip ratio (TyG-WHR), and triglyceride/high-density lipoprotein cholesterol(TG/HDL-c ratio). We used binary and multivariate ordered logistic regression models to estimate the association between different IR indices and the presence and severity of DR. Subject work characteristic curves were used to assess the predictive power of different IR indices for DR. RESULTS DR was present in 25.4% of participants. After adjusting for all covariates, per standard deviation (SD) increases in eGDR (ratio [OR] 0.38 [95% CI 0.32-0.44]), lnGDR (0.34 [0.27-0.42]) were negatively associated with the presence of DR. In contrast, per SD increases in METS-IR (1.97 [1.70-2.28]), TyG-BMI (1.94 [1.68-2.25]), TyG-WHR (2.34 [2.01-2.72]) and TG/HDL-c ratio (1.21 [1.08-1.36]) were positively associated with the presence of DR. eGDR was strongly associated with severity of DR. Of all variables, eGDR had the strongest diagnostic value for DR (AUC = 0.757). CONCLUSIONS Of the six IR indices, eGDR was significantly associated with the presence and severity of DR in patients with type 2 diabetes. eGDR has a good predictive value for DR. Thus, eGDR maybe a stronger marker of DR.
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Affiliation(s)
- Yu-Xin Xu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Sheng-Dan Pu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Yi-Tong Zhang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Xue-Wei Tong
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Xiao-Tong Sun
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Yong-Yan Shan
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Xin-Yuan Gao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
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13
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Zhou J, Zhu L, Li Y. Association between the triglyceride glucose index and diabetic retinopathy in type 2 diabetes: a meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1302127. [PMID: 38130393 PMCID: PMC10733479 DOI: 10.3389/fendo.2023.1302127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 10/25/2023] [Indexed: 12/23/2023] Open
Abstract
The triglyceride-glucose (TyG) index is an accessible and reliable surrogate indicator of insulin resistance and is strongly associated with diabetes. However, its relationship with diabetic retinopathy (DR) remains controversial. This meta-analysis aimed to assess the relationship between the TyG index and the prevalence of DR. Initial studies were searched from PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) electronic databases. The retrieval time range was from the establishment of the database to June 2023. Pooled estimates were derived using a random-effects model and reported as odds ratio (OR) with 95% confidence intervals (CIs). Two researchers independently assessed the methodological quality of the included studies. The Newcastle-Ottawa Quality Scale (NOS) was utilized to assess cohort studies or case-control studies. The Agency for Healthcare Research and Quality (AHRQ) methodology checklist was applied to assess cross-sectional studies. Ten observational studies encompassing 13716 patients with type 2 diabetes were included in the meta-analysis. The results showed that a higher TyG index increased the risk of DR compared with a low TyG index (OR: 2.34, 95% CI: 1.31-4.19, P < 0.05). When the index was analyzed as a continuous variable, consistent results were observed (OR: 1.48, 95% CI: 1.12-1.97, P < 0.005). There was no significant effect on the results of the sensitivity analyses excluding one study at a time (P all < 0.05). A higher TyG index may be associated with an increased prevalence of DR in patients with type 2 diabetes. However, high-quality cohort or case-control studies are needed to further substantiate this evidence. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023432747.
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Affiliation(s)
- Jianlong Zhou
- Department of Traditional Chinese Medicine, People’s Hospital of Deyang City, Deyang, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yadi Li
- Department of Traditional Chinese Medicine, People’s Hospital of Deyang City, Deyang, China
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Mohammad G, Kumar J, Kowluru RA. Mitochondrial Genome-Encoded Long Noncoding RNA Cytochrome B and Mitochondrial Dysfunction in Diabetic Retinopathy. Antioxid Redox Signal 2023; 39:817-828. [PMID: 37464864 PMCID: PMC10654995 DOI: 10.1089/ars.2023.0303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 06/22/2023] [Indexed: 07/20/2023]
Abstract
Aims: Mitochondrial dysfunction is closely associated with the development of diabetic complications. In diabetic retinopathy, electron transport chain is compromised and mitochondrial DNA (mtDNA) is damaged, downregulating transcription of mtDNA-encoded cytochrome B (CYTB) and its antisense long noncoding RNA, long noncoding RNA cytochrome B (LncCytB). Our goal was to investigate the role of LncCytB in the regulation of CYTB and mitochondrial function in diabetic retinopathy. Methods: Using human retinal endothelial cells, genetically manipulated for LncCytB (overexpression or silencing), the effect of high glucose (20 mM d-glucose) on LncCytB-CYTB interactions (by chromatin isolation by RNA purification), CYTB gene expression (by real-time quantitative polymerase chain reaction), complex III activity, mitochondrial free radicals, and oxygen consumption rate (OCR, by Seahorse XF analyzer) was investigated. Key results were confirmed in the retinal microvessels from streptozotocin-induced diabetic mice. Results: High glucose decreased LncCytB-CYTB interactions, and while LncCytB overexpression ameliorated glucose-induced decrease in CYTB gene transcripts, complex III activity and OCR and increase in mitochondrial reactive oxygen species, LncCytB-siRNA further attenuated CYTB gene transcription, complex III activity, and OCR. Similar decrease in LncCytB-CYTB interactions and CYTB transcription was observed in diabetic mice. Furthermore, maintenance of mitochondrial homeostasis by overexpressing superoxide dismutase or sirtuin 1 in mice ameliorated diabetes-induced decrease in LncCytB-CYTB interactions and CYTB gene transcripts, and also improved complex III activity and mitochondrial respiration. Innovation and Conclusion: LncCytB downregulation in hyperglycemic milieu downregulates CYTB transcription, which inhibits complex III activity and compromises mitochondrial stability and OCR. Thus, preventing LncCytB downregulation in diabetes has potential of inhibiting the development of diabetic retinopathy, possibly via maintaining mitochondrial respiration. Antioxid. Redox Signal. 39, 817-828.
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Affiliation(s)
- Ghulam Mohammad
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, USA
| | - Jay Kumar
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, USA
| | - Renu A. Kowluru
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, USA
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15
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Sadikan MZ, Abdul Nasir NA, Lambuk L, Mohamud R, Reshidan NH, Low E, Singar SA, Mohmad Sabere AS, Iezhitsa I, Agarwal R. Diabetic retinopathy: a comprehensive update on in vivo, in vitro and ex vivo experimental models. BMC Ophthalmol 2023; 23:421. [PMID: 37858128 PMCID: PMC10588156 DOI: 10.1186/s12886-023-03155-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/26/2023] [Indexed: 10/21/2023] Open
Abstract
Diabetic retinopathy (DR), one of the leading causes of visual impairment and blindness worldwide, is one of the major microvascular complications in diabetes mellitus (DM). Globally, DR prevalence among DM patients is 25%, and 6% have vision-threatening problems among them. With the higher incidence of DM globally, more DR cases are expected to be seen in the future. In order to comprehend the pathophysiological mechanism of DR in humans and discover potential novel substances for the treatment of DR, investigations are typically conducted using various experimental models. Among the experimental models, in vivo models have contributed significantly to understanding DR pathogenesis. There are several types of in vivo models for DR research, which include chemical-induced, surgical-induced, diet-induced, and genetic models. Similarly, for the in vitro models, there are several cell types that are utilised in DR research, such as retinal endothelial cells, Müller cells, and glial cells. With the advancement of DR research, it is essential to have a comprehensive update on the various experimental models utilised to mimic DR environment. This review provides the update on the in vitro, in vivo, and ex vivo models used in DR research, focusing on their features, advantages, and limitations.
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Affiliation(s)
- Muhammad Zulfiqah Sadikan
- Department of Pharmacology, Faculty of Medicine, Manipal University College Malaysia (MUCM), Bukit Baru, 75150, Melaka, Malaysia
| | - Nurul Alimah Abdul Nasir
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA, 47000, Sungai Buloh, Selangor, Malaysia.
| | - Lidawani Lambuk
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Nur Hidayah Reshidan
- School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, 40450, Shah Alam, Selangor, Malaysia
| | - Evon Low
- Ageing Biology Centre, Newcastle University, NE1 7RU, Newcastle upon Tyne, UK
| | - Saiful Anuar Singar
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, 32306, Tallahassee, FL, USA
| | - Awis Sukarni Mohmad Sabere
- Kulliyyah of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Bandar Indera Mahkota, 25200, Kuantan, Pahang, Malaysia
| | - Igor Iezhitsa
- School of Medicine, International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov sq. 1, 400131 , Volgograd, Russian Federation
| | - Renu Agarwal
- School of Medicine, International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
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Puddu A, Maggi DC. Klotho: A new therapeutic target in diabetic retinopathy? World J Diabetes 2023; 14:1027-1036. [PMID: 37547589 PMCID: PMC10401458 DOI: 10.4239/wjd.v14.i7.1027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Klotho (Kl) is considered an antiaging gene, mainly for the inhibition of the insulin-like growth factor-1 signaling. Kl exists as full-length transmembrane, which acts as co-receptor for fibroblast growth factor receptor, and in soluble forms (sKl). The sKl may exert pleiotropic effects on organs and tissues by regulating several pathways involved in the pathogenesis of diseases associated with oxidative and inflammatory state. In diabetic Patients, serum levels of Kl are significantly decreased compared to healthy subjects, and are related to duration of diabetes. In diabetic retinopathy (DR), one of the most common microvascular complications of type 2 diabetes, serum Kl levels are negatively correlated with progression of the disease. A lot of evidences showed that Kl regulates several mechanisms involved in maintaining homeostasis and functions of retinal cells, including phagocytosis, calcium signaling, secretion of vascular endothelial growth factor A (VEGF-A), maintenance of redox status, and melanin biosynthesis. Experimental data have been shown that Kl exerts positive effects on several mechanisms involved in onset and progression of DR. In particular, treatment with Kl: (1) Prevents apoptosis induced by oxidative stress in human retinal endothelial cells and in retinal pigment epithelium (RPE) cells; (2) reduces secretion of VEGF-A by RPE cells; and (3) decreases subretinal fibrosis and preserves autophagic activity. Therefore, Kl may become a novel biomarker and a good candidate for the treatment of DR.
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Affiliation(s)
- Alessandra Puddu
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Davide Carlo Maggi
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
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17
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Oudeh S, Javahery Vayghan A, Ahmadi-Hamedani M. Duration of the diabetic state altered platelet indices from baseline values in a streptozotocin-induced rat model for type 1 diabetes mellitus. Vet Clin Pathol 2023; 52:236-242. [PMID: 36973508 DOI: 10.1111/vcp.13229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 11/08/2022] [Accepted: 12/07/2022] [Indexed: 03/29/2023]
Abstract
BACKGROUND Changes in platelet indices in naturally occurring type I diabetes mellitus (T1DM) have been described in several studies. In this study, platelet indices such as platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), platelet distribution width (PDW), and MPV to PLT ratio were investigated according to diabetic duration after streptozotocin (STZ)-induced T1DM, as well as for their correlation with glucose. METHODS Forty healthy adult Wistar rats were randomly assigned to four experimental groups of ten (5 rats of each sex), including the control group, the 7, 14, and 28 days diabetic groups (D7, D14, and D28, respectively). RESULTS In diabetic groups, plasma glucose was significantly higher than in control (P < 0.01). D7, D14, and D28 groups presented significantly lower PLT than the control (P < 0. 01). A significant decrease in PCT was observed in D14 and D28 females (P < 0.05). Mean platelet volume was significantly higher in the D28 group than in to control. D28 females also showed a significant difference in PLT, MPV, and the MPV-to-PLT ratio compared with D7 females (P < 0.05). A comparison between D28 females and males showed a significant difference in PDW (P < 0.05). Both females and males showed a significant correlation between glucose and PLT, PCT, MPV, and the MPV-to-PLT ratio. CONCLUSIONS Platelet indices change significantly with the duration of diabetes compared with the baseline values, and female and male rats did not have significant differences in platelet indices in any period except the 28 days.
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Affiliation(s)
- Sahar Oudeh
- Faculty of Veterinary Medicine, Department of Pathobiology, Semnan University, Semnan, Iran
| | - Abbas Javahery Vayghan
- Faculty of Veterinary Medicine, Department of Pathobiology, Semnan University, Semnan, Iran
| | - Mahmood Ahmadi-Hamedani
- Faculty of Veterinary Medicine, Department of Clinical Sciences, Semnan University, Semnan, Iran
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18
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Li Z, Yu H, Liu C, Wang C, Zeng X, Yan J, Sun Y. Efficiency co-delivery of ellagic acid and oxygen by a non-invasive liposome for ameliorating diabetic retinopathy. Int J Pharm 2023; 641:122987. [PMID: 37207860 DOI: 10.1016/j.ijpharm.2023.122987] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 05/21/2023]
Abstract
Diabetic retinopathy (DR) is one of the serious complications of diabetes, which has become the fourth leading cause of vision loss worldwide. Current treatment of DR relies on intravitreal injections of antiangiogenic agents, which has made considerable achievements in reducing visual impairment. However, long-term invasive injections require advanced technology and can lead to poor patient compliance as well as the incidence of ocular complications including bleeding, endophthalmitis, retinal detachment and others. Hence, we developed non-invasive liposomes (EA-Hb/TAT&isoDGR-Lipo) for efficiency co-delivery of ellagic acid and oxygen, which can be administered intravenously or by eye drops. Among that, ellagic acid (EA), as an aldose reductase inhibitor, could remove excessive reactive oxygen species (ROS) induced by high glucose for preventing retinal cell apoptosis, as well as reduce retinal angiogenesis through the blockage of VEGFR2 signaling pathway; carried oxygen could ameliorate DR hypoxia, and further enhanced the anti-neovascularization efficacy. Our results showed that EA-Hb/TAT&isoDGR-Lipo not only effectively protected retinal cells from high glucose-induced damage, but also inhibited VEGF-induced vascular endothelial cells migration, invasion, and tube formation in vitro. In addition, in a hypoxic cell model, EA-Hb/TAT&isoDGR-Lipo could reverse retinal cell hypoxia, thereby reducing the expression of VEGF. Significantly, after being administered as an injection or eye drops, EA-Hb/TAT&isoDGR-Lipo obviously ameliorated the structure (central retinal thickness and retinal vascular network) of retina by eliminating ROS and down-regulating the expression of GFAP, HIF-1α, VEGF and p-VEGFR2 in a DR mouse model. In summary, EA-Hb/TAT&isoDGR-Lipo holds great potentials in improvement of DR, which provides a novel approach for the treatment of DR.
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Affiliation(s)
- Zhipeng Li
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Hongli Yu
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Chaolong Liu
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Changduo Wang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Xianhu Zeng
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Jianqin Yan
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
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Nunes AR, Costa EC, Alves G, Silva LR. Nanoformulations for the Delivery of Dietary Anthocyanins for the Prevention and Treatment of Diabetes Mellitus and Its Complications. Pharmaceuticals (Basel) 2023; 16:ph16050736. [PMID: 37242519 DOI: 10.3390/ph16050736] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/06/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetes mellitus (DM) is a metabolic disease characterized by abnormal blood glucose levels-hyperglycemia, caused by a lack of insulin secretion, impaired insulin action, or a combination of both. The incidence of DM is increasing, resulting in billions of dollars in annual healthcare costs worldwide. Current therapeutics aim to control hyperglycemia and reduce blood glucose levels to normal. However, most modern drugs have numerous side effects, some of which cause severe kidney and liver problems. On the other hand, natural compounds rich in anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin) have also been used for the prevention and treatment of DM. However, lack of standardization, poor stability, unpleasant taste, and decreased absorption leading to low bioavailability have hindered the application of anthocyanins as therapeutics. Therefore, nanotechnology has been used for more successful delivery of these bioactive compounds. This review summarizes the potential of anthocyanins for the prevention and treatment of DM and its complications, as well as the strategies and advances in the delivery of anthocyanins using nanoformulations.
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Affiliation(s)
- Ana R Nunes
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
- CNC-Centre for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Elisabete C Costa
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Gilberto Alves
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Luís R Silva
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
- CPIRN-UDI-IPG-Research Unit for Inland Development, Center for Potential and Innovation of Natural Resources, Polytechnic of Guarda, 6300-554 Guarda, Portugal
- CIEPQPF, Department of Chemical Engineering, University of Coimbra, Pólo II-Pinhal de Marrocos, 3030-790 Coimbra, Portugal
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Rodent Models of Diabetic Retinopathy as a Useful Research Tool to Study Neurovascular Cross-Talk. BIOLOGY 2023; 12:biology12020262. [PMID: 36829539 PMCID: PMC9952991 DOI: 10.3390/biology12020262] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
Diabetes is a group of metabolic diseases leading to dysfunction of various organs, including ocular complications such as diabetic retinopathy (DR). Nowadays, DR treatments involve invasive options and are applied at the sight-threatening stages of DR. It is important to investigate noninvasive or pharmacological methods enabling the disease to be controlled at the early stage or to prevent ocular complications. Animal models are useful in DR laboratory practice, and this review is dedicated to them. The first part describes the characteristics of the most commonly used genetic rodent models in DR research. The second part focuses on the main chemically induced models. The authors pay particular attention to the streptozotocin model. Moreover, this section is enriched with practical aspects and contains the current protocols used in research in the last three years. Both parts include suggestions on which aspect of DR can be tested using a given model and the disadvantages of each model. Although animal models show huge variability, they are still an important and irreplaceable research tool. Note that the choice of a research model should be thoroughly considered and dependent on the aspect of the disease to be analyzed.
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Bioactivity-Guided Fractionation and Identification of Antidiabetic Compound of Syzygium polyanthum (Wight.)'s Leaf Extract in Streptozotocin-Induced Diabetic Rat Model. Molecules 2022; 27:molecules27206814. [PMID: 36296407 PMCID: PMC9609764 DOI: 10.3390/molecules27206814] [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: 08/01/2022] [Revised: 09/21/2022] [Accepted: 10/05/2022] [Indexed: 12/06/2022] Open
Abstract
(1) Background: An earlier study on the hypoglycemic activity of S. polyanthum (Wight.) leaf methanol extract identified squalene as the major chemical compound. The present study was conducted to assess the hypoglycemic effect of fractions and subfractions of the methanol extract of S. polyanthum compared to the squalene using a bioassay-guided in vivo study. (2) Methods: The methanol extract was fractionated using the liquid−liquid fractionation method. Streptozotocin-induced type 1 diabetic rat was used to study the hypoglycemic effect. (3) Results: The findings showed that chloroform fraction significantly (p < 0.05) lowered blood glucose levels of diabetic rats as compared to the control. Further fractionation of chloroform fraction yielded subfraction-1 and -2, whereby subfraction-1 exhibited a higher blood-glucose-lowering effect. The lipid profile test showed that the total cholesterol level of subfraction-1 and squalene-treated groups decreased significantly (p < 0.05). An immunohistochemistry study revealed that none of the treatments regenerated pancreatic β-cells. Gas chromatography−mass spectrophotometer analysis identified the presence of squalene in the active methanol extract, chloroform fraction, and subfraction-1. In silico analysis revealed a higher affinity of squalene against protein receptors that control lipid metabolism than metformin. (4) Conclusions: Data obtained from the present work suggested the crude methanol extract exerted the highest hypoglycemic effect compared to fraction, subfraction, and squalene, confirming synergistic effect may be responsible for the hypoglycemic activity of S. polyanthum.
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Regulation of serine palmitoyl-transferase and Rac1-Nox2 signaling in diabetic retinopathy. Sci Rep 2022; 12:16740. [PMID: 36202842 PMCID: PMC9537524 DOI: 10.1038/s41598-022-20243-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/12/2022] [Indexed: 11/23/2022] Open
Abstract
Hyperlipidemia is considered as one of the major systemic factors associated with the development of diabetic retinopathy, and animal models have documented that its presence in a hyperglycemic environment exacerbates cytosolic ROS production (via activation of the Rac1–Nox2 axis) and mitochondrial damage. Hyperglycemia also accelerates Rac1 transcription via dynamic DNA methylation–hydroxymethylation of its promoter. In diabetes, ceramide metabolism in the retina is impaired and its accumulation is increased. Our aim was to investigate the effect of inhibition of the rate limiting enzyme of the de novo ceramide biosynthesis, serine palmitoyl-transferase (SPT), on Rac1 activation in diabetic retinopathy. Using human retinal endothelial cells, transfected with SPT-siRNA, and incubated in 20 mM d-glucose in the presence or absence of 50 µM palmitate (glucolipotoxic and glucotoxic, respectively), activities of Rac1 and Nox2, and ROS levels were quantified. For Rac1 transcriptional activation, 5 hydroxymethyl cytosine (5hmC) levels at its promoter were quantified. Key parameters were confirmed in retinal microvessels from streptozotocin-induced diabetic mice on a normal diet (type 1 diabetic model) or on a high-fat diet (45% kcal, type 2 diabetic model), injected intravitreally with SPT-siRNA. Compared to normal glucose, cells in high glucose, with or without palmitic acid, had increased Rac1–Nox2–ROS signaling, Rac1 transcripts and 5hmC levels at its promoter. Inhibition of SPT by SPT-siRNA or myriocin prevented glucotoxic- and glucolipotoxic-induced increase in Rac1–Nox2–ROS signaling and 5hmC at the Rac1 promoter. Similarly, in both type 1 and type 2 diabetic mouse models, SPT-siRNA attenuated the increase in the Rac1–Nox2–ROS axis and 5hmC at the Rac1 promoter. Thus, inhibition of the rate limiting enzyme of ceramide de novo biosynthesis, SPT, regulates activation of DNA methylation–hydroxymethylation machinery and prevents increased Rac1 transcription. This ameliorates the activation of Rac1–Nox2 signaling and protects the mitochondria from damaging cytosolic ROS, which prevents accelerated capillary cell loss. These results further raise the importance of regulating lipid levels in diabetic patients with dyslipidemia.
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Zhu D, Zou W, Cao X, Xu W, Lu Z, Zhu Y, Hu X, Hu J, Zhu Q. Ferulic acid attenuates high glucose-induced apoptosis in retinal pigment epithelium cells and protects retina in db/db mice. PeerJ 2022; 10:e13375. [PMID: 35669949 PMCID: PMC9165606 DOI: 10.7717/peerj.13375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 04/13/2022] [Indexed: 01/13/2023] Open
Abstract
Background Herein, we aimed to present evidence that Ferulic acid (FA), a phenolic acid, can alleviate high glucose (HG)-induced retinal pigment epithelium (RPE) cell apoptosis and protect retina in db/db mice. Methods ARPE-19 cells (a human RPE cell line) were divided into four groups: control group; HG group (30 mmol/L glucose); HG+FA group (30 mmol/L glucose and 10 mmol/L FA). Cell viability and apoptosis were detected using CCK-8 and Annexin-5 staining, respectively. Apoptosis-related markers including P53, BAX and Bcl2 were examined by RT-qPCR, western blot and immunohistochemistry. Totally, 30 male db/db mice were randomly divided into db/db group (5 ml/kg saline) and FA group (0.05 g/kg FA). After treatment for 2 months, retinal samples were subjected to hematoxylin and eosin (H&E) and Masson staining. Moreover, immunofluorescence was used to detect apoptosis-related markers. Blood samples were collected for measuring cholesterol, triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels. Results FA treatment markedly increased cell viability and suppressed cell apoptosis of ARPE-19 cells compared to the HG-exposed group. Furthermore, FA ameliorated the abnormal expression levels of P53, BAX and Bcl2 in HG-induced ARPE-19 cells. In animal models, FA attenuated pathological changes in the retina tissues of diabetic mice. Consistent with in vitro models, FA significantly ameliorated the expression of apoptosis-related markers in retina tissues. Biochemical test results showed that FA reduced hyperlipidemia in diabetic mice. Conclusion Our findings suggest that FA alleviates HG-induced apoptosis in RPE cells and protects retina in db/db mice, which can be associated with P53 and BAX inactivation and Bcl2 activation.
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Affiliation(s)
- Dejun Zhu
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
| | - Wenqing Zou
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
| | - Xiangmei Cao
- Department of Pathology, School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Weigang Xu
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
| | - Zhaogang Lu
- Department of Pharmacy, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Yan Zhu
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
| | - Xiaowen Hu
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
| | - Jin Hu
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
| | - Qing Zhu
- Department of Ophthalmology, Ning Xia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye), Yinchuan, Ningxia, China
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Liu Y, Huang H, Sun Y, Li Y, Luo B, Cui J, Zhu M, Bi F, Chen K, Liu Y. Monosodium Glutamate-Induced Mouse Model With Unique Diabetic Retinal Neuropathy Features and Artificial Intelligence Techniques for Quantitative Evaluation. Front Immunol 2022; 13:862702. [PMID: 35572527 PMCID: PMC9092070 DOI: 10.3389/fimmu.2022.862702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 03/17/2022] [Indexed: 11/26/2022] Open
Abstract
Objective To establish an artificial intelligence-based method to quantitatively evaluate subtle pathological changes in retinal nerve cells and synapses in monosodium glutamate (MSG) mice and provide an effective animal model and technique for quantitative evaluation of retinal neurocytopathies. Methods ICR mice were subcutaneously injected with MSG to establish a model of metabolic syndrome. We then established a mouse model of type 1 diabetes, type 2 diabetes, and KKAy mouse model as control. The HE sections of the retina were visualized using an optical microscope. AI technology was used for quantitative evaluation of the retinal lesions in each group of rats. The surface area custom parameters of the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL) were defined as SR, SIPL, SINL, and SOPL, respectively. Their heights were defined as HR, HIPL, HINL, and HOPL, and the number of ganglion cells was defined as A. Then, the attention-augmented fully convolutional Unet network was used to segment the retinal HE images, and AI technology to identify retinal neurocytopathies quantitatively. Results The attention-augmented fully convolutional Unet network increased PA and IOU parameters for INL, OPL, RNFL, and ganglion cells and was superior in recognizing fine structures. A quantitative AI identification of the height of each layer of the retina showed that the heights of the IPL and INL of the MSG model were significantly less than those of the control groups; the retinas of the other diabetic models did not exhibit this pathological feature. The RNFLs of type 2 diabetes were thinner, and the characteristics of retinopathy were not obvious in the other animal models. The pathological changes seen on HE images were consistent with the results of the quantitative AI evaluation. Immunohistochemistry results showed that NMDAR2A, GluR2, and NRG1 were significantly downregulated in the retina of MSG mice. Conclusions The MSG retinopathy model is closely associated with neurotransmitter abnormalities and exhibits important characteristics of retinal neurodegeneration, making it suitable for studying retinal neurocytopathies. The AI recognition technology for retinal images established in the present study can be used for the quantitative and objective evaluation of drug efficacy.
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Affiliation(s)
- Yanfei Liu
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hui Huang
- Beijing Duan-Dian Pharmaceutical Research & Development Co., Ltd., Beijing, China
| | - Yu Sun
- North China University of Technology, Beijing, China
| | - Yiwen Li
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Binyu Luo
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Cui
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Mengmeng Zhu
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fukun Bi
- North China University of Technology, Beijing, China
| | - Keji Chen
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yue Liu
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Niewiadomska J, Gajek-Marecka A, Gajek J, Noszczyk-Nowak A. Biological Potential of Polyphenols in the Context of Metabolic Syndrome: An Analysis of Studies on Animal Models. BIOLOGY 2022; 11:biology11040559. [PMID: 35453758 PMCID: PMC9029039 DOI: 10.3390/biology11040559] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/31/2022] [Accepted: 04/05/2022] [Indexed: 02/04/2023]
Abstract
Metabolic syndrome (MetS) is a disease that has a complex etiology. It is defined as the co-occurrence of several pathophysiological disorders, including obesity, hyperglycemia, hypertension, and dyslipidemia. MetS is currently a severe problem in the public health care system. As its prevalence increases every year, it is now considered a global problem among adults and young populations. The treatment of choice comprises lifestyle changes based mainly on diet and physical activity. Therefore, researchers have been attempting to discover new substances that could help reduce or even reverse the symptoms when added to food. These attempts have resulted in numerous studies. Many of them have investigated the bioactive potential of polyphenols as a "possible remedy", stemming from their antioxidative and anti-inflammatory effects and properties normalizing carbohydrate and lipid metabolism. Polyphenols may be supportive in preventing or delaying the onset of MetS or its complications. Additionally, the consumption of food rich in polyphenols should be considered as a supplement for antidiabetic drugs. To ensure the relevance of the studies on polyphenols' properties, mechanisms of action, and potential human health benefits, researchers have used laboratory animals displaying pathophysiological changes specific to MetS. Polyphenols or their plant extracts were chosen according to the most advantageous mitigation of pathological changes in animal models best reflecting the components of MetS. The present paper comprises an overview of animal models of MetS, and promising polyphenolic compounds whose bioactive potential, effect on metabolic pathways, and supplementation-related benefits were analyzed based on in vivo animal models.
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Affiliation(s)
- Joanna Niewiadomska
- Doctoral School of Wroclaw, University of Environmental and Life Sciences, 50-375 Wroclaw, Poland
- Correspondence:
| | | | - Jacek Gajek
- Department of Emergency Medical Service, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Agnieszka Noszczyk-Nowak
- Department of Internal and Diseases with Clinic for Horses, Dogs, and Cats, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, 50-375 Wroclaw, Poland;
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Zhang L, Hu Y, An Y, Wang Q, Liu J, Wang G. The Changes of Lipidomic Profiles Reveal Therapeutic Effects of Exenatide in Patients With Type 2 Diabetes. Front Endocrinol (Lausanne) 2022; 13:677202. [PMID: 35432194 PMCID: PMC9009038 DOI: 10.3389/fendo.2022.677202] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/07/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE Exenatide has been demonstrated beneficial effects on patients with type 2 diabetes mellitus (T2DM) regarding lipid metabolism. However, the potential mechanism remains unclear. We used a lipidomic approach to evaluate lipid changes in response to treatment with exenatide in T2DM patients. METHODS Serum lipidomic profiles of 35 newly diagnosed T2DM patients (before and after exenatide treatment) and 20 age-matched healthy controls were analyzed by ultrahigh-performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry. RESULTS A total of 45 lipid species including sphingomyelins (SMs), ceramides (CERs), lysophosphatidylcholines (LPCs), phosphatidylethanolamines (PEs), lysophosphatidylethanolamines (LPEs) and phosphatidylcholines (PCs) were identified in all participants. Compared to the healthy controls, 13 lipid species [SM (d18:1/18:0, d18:1/18:1), Cer (d18:1/18:0, d18:1/16:0, d18:1/20:0, d18:1/24:1), LPC (15:0, 16:0, 17:0), PC (19:0/19:0), LPE (18:0) and PE (16:0/22:6, 18:0/22:6)] were markedly increased in the T2DM group, while PE (17:0/17:0) and PC (18:1/18:0) were decreased (P < 0.05). The serum SM (d18:1/18:0, d18:1/18:1), LPC (16:0), and LPE (18:0) were significantly decreased after exenatide treatment, which was accompanied by the amelioration of lipids and glycemic parameters (TC, LDL-C, ApoA-I, FCP and HbA1c) in T2DM patients. The chord diagrams showed distinct correlation patterns between lipid classes and subclasses among healthy controls, T2DM patients before and after exenatide treatment. CONCLUSION Our results revealed that the therapeutic benefits of exenatide on T2DM might be involved in the improved lipid metabolism, especially SM, LPC, and LPE. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT03297879.
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Affiliation(s)
| | | | | | | | - Jia Liu
- *Correspondence: Jia Liu, ; Guang Wang,
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MI S, GU J, CAO X, LI Y, XU Q, CHEN W, ZHANG Y. Regulatory mechanism of fermented wheat germ on lipid metabolism in hyperlipidemia rats via activation of AMPK pathway. FOOD SCIENCE AND TECHNOLOGY 2022. [DOI: 10.1590/fst.57222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Shengquan MI
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
| | - Junxia GU
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
| | - Xuelian CAO
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
| | - Yi LI
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
| | - Qile XU
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
| | - Wen CHEN
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
| | - Yanzhen ZHANG
- Beijing Union University, China; Beijing Key Laboratory of Bioactive Substances and Functional Foods, China
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Gao S, Ma X, Ji F, Chen C, Jiang D, Xu Y, Song X, Wang W, Lin X, Tian H, Zhuo C, Ye X, Yu H. Antipsychotics With Different Chemical Structures Cause Different Degrees of Functional Impairments in the Primary Visual Cortex in a Murine Model: A Pilot Study. PSYCHIAT CLIN PSYCH 2021; 31:364-369. [PMID: 38765639 PMCID: PMC11079715 DOI: 10.5152/pcp.2021.20022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 11/21/2020] [Indexed: 05/22/2024] Open
Abstract
Background Antipsychotic medications can impair vision in patients with schizophrenia. However, little is known regarding the pharmacodynamics of antipsychotics in the primary visual cortex. We aimed to study the pharmacodynamics of antipsychotics in the visual cortex in a murine model. Methods We used an adapted 2-photon imaging technique to observe changes in calcium dynamics induced by 4 antipsychotics (olanzapine, risperidone, aripiprazole, and amisulpride) in the primary visual cortex of healthy and schizophrenic C57BL/6 mice. Visual function was further assessed by using a novel object recognition test. Results All 4 antipsychotics decreased calcium activity in the primary visual cortex and reduced visual recognition test scores in healthy and schizophrenic mice. The most potent drug was olanzapine, followed by risperidone, aripiprazole, and amisulpride. All drugs showed significant differences between groups. Conclusion Our pilot study demonstrated that antipsychotics impair visual cortical function. This finding underscores the importance of monitoring for visual adverse events in patients receiving antipsychotic medications to treat schizophrenia.
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Affiliation(s)
- Si Gao
- Department of Psychiatry and Microimaging Center, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, China
| | - Xiaoyan Ma
- Department of Psychiatric-Neuroimaging-Genetics and Comorbidity Laboratory, Tianjin Anding Hospital, Tianjin, China
| | - Feng Ji
- Department of Psychiatry, School of Mental Health, Jining Medical University, Jining, Shandong Province, China
| | - Ce Chen
- Department of Psychiatry and Microimaging Center, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, China
| | - Deguo Jiang
- Department of Psychiatry and Microimaging Center, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, China
| | - Yong Xu
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- MDT Center for Cognitive Impairment and Sleep Disorders, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xueqin Song
- First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
- Biological Psychiatry International Joint Laboratory of Henan, Zhengzhou University, Zhengzhou, China
- Henan Psychiatric Transformational Research Key Laboratory, Zhengzhou University, Zhengzhou, China
| | - Wenqiang Wang
- Canadian and Chinese Joint Laboratory of Biological Psychiatry, Xiamen Xianye Hospital, Xiamen, Fujian Province, China
| | - Xiaodong Lin
- Department of Psychiatry and Microimaging Center, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, China
| | - Hongjun Tian
- Department of Psychiatry and Microimaging Center, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, China
- Department of Psychiatry, School of Mental Health, Jining Medical University, Jining, Shandong Province, China
| | - Chuanjun Zhuo
- Department of psychiatry, Tianjin Fourth Central Hospital, Tianjin, China
| | - Xinwu Ye
- Department of Psychiatric-Neuroimaging-Genetics and Comorbidity Laboratory, Tianjin Anding Hospital, Tianjin, China
| | - Haiping Yu
- Department of Psychiatric-Neuroimaging-Genetics and Comorbidity Laboratory, Tianjin Anding Hospital, Tianjin, China
- Department of psychiatry, Tianjin Fourth Central Hospital, Tianjin, China
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Cai ZY, Fu MD, Liu K, Duan XC. Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress. Int J Ophthalmol 2021; 14:1260-1273. [PMID: 34414093 DOI: 10.18240/ijo.2021.08.19] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022] Open
Abstract
Age-related eye diseases, including cataract, glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the leading causes of vision loss in the world. Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye. The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body. This pathway is also active in the development of age-related eye diseases. A variety of drugs have been shown to treat age-related eye diseases through the Keap1-Nrf2-ARE (Kelch-like ECH-Associating protein 1- nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway. This review describes the role of oxidative stress in the development of age-related eye diseases, the function and regulation of the Keap1-Nrf2-ARE pathway, and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.
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Affiliation(s)
- Zi-Yan Cai
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Meng-Die Fu
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Ke Liu
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Xuan-Chu Duan
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China.,Department of Ophthalmology, Changsha Aier Eye Hospital, Changsha 410011, Hunan Province, China
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Bu J, Zhang M, Wu Y, Jiang N, Guo Y, He X, He H, Jeyalatha MV, Reinach PS, Liu Z, Li W. High-Fat Diet Induces Inflammation of Meibomian Gland. Invest Ophthalmol Vis Sci 2021; 62:13. [PMID: 34398199 PMCID: PMC8374999 DOI: 10.1167/iovs.62.10.13] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose To determine if a high-fat diet (HFD) induces meibomian gland (MG) inflammation in mice. Methods Male C57BL/6J mice were fed a standard diet (SD), HFD, or HFD supplemented with the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist rosiglitazone for various durations. Body weight, blood lipid levels, and eyelid changes were monitored at regular intervals. MG sections were subjected to hematoxylin and eosin staining, LipidTox staining, TUNEL assay, and immunostaining. Quantitative RT-PCR and western blot analyses were performed to detect relative gene expression and signaling pathway activation in MGs. Results MG acinus accumulated more lipids in the mice fed the HFD. Periglandular CD45-positive and F4/80-positive cell infiltration were more evident in the HFD mice, and they were accompanied by upregulation of inflammation-related cytokines. PPAR-γ downregulation accompanied activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways in the HFD mice. There was increased acini cell apoptosis and mitochondria damage in mice fed the HFD. MG inflammation was ameliorated following a shift to the standard diet and rosiglitazone treatment in the mice fed the HFD. Conclusions HFD-induced declines in PPAR-γ expression and MAPK and NF-κB signaling pathway activation resulted in MG inflammation and dysfunction in mice.
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Affiliation(s)
- Jinghua Bu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.,Eye Institute of Xiamen University, Xiamen, Fujian, China.,School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Minjie Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Yang Wu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.,Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, Fujian, China
| | - Nan Jiang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Yuli Guo
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Xin He
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Hui He
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - M Vimalin Jeyalatha
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Peter Sol Reinach
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zuguo Liu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.,Eye Institute of Xiamen University, Xiamen, Fujian, China
| | - Wei Li
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.,Eye Institute of Xiamen University, Xiamen, Fujian, China
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31
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Lee ES, Kang JS, Kim HM, Kim SJ, Kim N, Lee JO, Kim HS, Lee EY, Chung CH. Dehydrozingerone inhibits renal lipotoxicity in high-fat diet-induced obese mice. J Cell Mol Med 2021; 25:8725-8733. [PMID: 34382326 PMCID: PMC8435425 DOI: 10.1111/jcmm.16828] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022] Open
Abstract
Ectopic fat accumulation in the kidneys causes oxidative stress, inflammation and cell death. Dehydrozingerone (DHZ) is a curcumin analog that exhibits antitumour, antioxidant and antidiabetic effects. However, the efficacy of DHZ in diabetic nephropathy (DN) is unknown. Here, we verified the efficacy of DHZ on DN. We divided the experimental animals into three groups: regular diet, 60% high‐fat diet (HFD) and HFD with DHZ for 12 weeks. We analysed levels of renal triglycerides and urinary albumin and albumin‐creatinine ratio, renal morphological changes and molecular changes via real‐time polymerase chain reaction and immunoblotting. Furthermore, high glucose (HG)‐ or palmitate (PA)‐stimulated mouse mesangial cells or mouse podocytes were treated with DHZ for 24 h. As a result, DHZ markedly reduced renal glycerol accumulation and albuminuria excretion through improvement of thickened glomerular basement membrane, podocyte loss and slit diaphragm reduction. In the renal cortex in the HFD group, phospho‐AMPK and nephrin expression reduced, whereas arginase 2 and CD68 expression increased; however, these changes were recovered after DHZ administration. Increased reactive oxygen species (ROS) stimulated by HG or PA in podocytes was inhibited by DHZ treatment. Collectively, these findings indicate that DHZ ameliorates DN via inhibits of lipotoxicity‐induced inflammation and ROS formation.
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Affiliation(s)
- Eun Soo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institution of Genetic Cohort, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jeong Suk Kang
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.,Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | | | - Su Jin Kim
- Department of Anatomy, Korea University College of Medicine, Seoul, Korea
| | - Nami Kim
- Western Seoul Center, Korea Basic Science Institute, Seoul, Korea
| | - Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, Seoul, Korea
| | - Hyeon Soo Kim
- Department of Anatomy, Korea University College of Medicine, Seoul, Korea
| | - Eun Young Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.,Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Choon Hee Chung
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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32
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NR4A1 enhances MKP7 expression to diminish JNK activation induced by ROS or ER-stress in pancreatic β cells for surviving. Cell Death Discov 2021; 7:133. [PMID: 34088892 PMCID: PMC8178316 DOI: 10.1038/s41420-021-00521-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/18/2021] [Accepted: 05/13/2021] [Indexed: 12/03/2022] Open
Abstract
Under adverse conditions, such as sustained or chronic hyperglycemia or hyperlipidemia, ROS (reactive oxygen species) or/and ER-stress (endoplasmic reticulum stress) will be induced in pancreatic β cells. ROS or ER-stress damages β-cells even leads to apoptosis. Previously we found ROS or ER-stress resulted in JNK activation in β cells and overexpressing NR4A1 in MIN6 cells reduced JNK activation via modulating cbl-b expression and subsequent degrading the upstream JNK kinase (MKK4). To search other possible mechanisms, we found the mRNA level and protein level of MKP7 (a phosphatase for phospho-JNK) were dramatic reduced in pancreatic β cells in the islets from NR4A1 KO mice compared with that from wild type mice. To confirm what we found in animals, we applied pancreatic β cells (MIN6 cells) and found that the expression of MKP7 was increased in NR4A1-overexpression MIN6 cells. We further found that knocking down the expression of MKP7 increased the p-JNK level in pancreatic β cells upon treatment with TG or H2O2. After that, we figured out that NR4A1 did enhance the transactivation of the MKP7 promoter by physical association with two putative binding sites. In sum, NR4A1 attenuates JNK phosphorylation incurred by ER-stress or ROS partially via enhancing MKP7 expression, potentially decreases pancreatic β cell apoptosis induced by ROS or ER-stress. Our finding provides a clue for diabetes prevention.
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33
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Kowluru RA. Diabetic Retinopathy and NADPH Oxidase-2: A Sweet Slippery Road. Antioxidants (Basel) 2021; 10:783. [PMID: 34063353 PMCID: PMC8156589 DOI: 10.3390/antiox10050783] [Citation(s) in RCA: 16] [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: 04/08/2021] [Revised: 05/03/2021] [Accepted: 05/13/2021] [Indexed: 11/17/2022] Open
Abstract
Diabetic retinopathy remains the leading cause of vision loss in working-age adults. The multi-factorial nature of the disease, along with the complex structure of the retina, have hindered in elucidating the exact molecular mechanism(s) of this blinding disease. Oxidative stress appears to play a significant role in its development and experimental models have shown that an increase in cytosolic Reacttive Oxygen Speies (ROS) due to the activation of NADPH oxidase 2 (Nox2), is an early event, which damages the mitochondria, accelerating loss of capillary cells. One of the integral proteins in the assembly of Nox2 holoenzyme, Rac1, is also activated in diabetes, and due to epigenetic modifications its gene transcripts are upregulated. Moreover, addition of hyperlipidemia in a hyperglycemic milieu (type 2 diabetes) further exacerbates Rac1-Nox2-ROS activation, and with time, this accelerates and worsens the mitochondrial damage, ultimately leading to the accelerated capillary cell loss and the development of diabetic retinopathy. Nox2, a multicomponent enzyme, is a good candidate to target for therapeutic interventions, and the inhibitors of Nox2 and Rac1 (and its regulators) are in experimental or clinical trials for other diseases; their possible use to prevent/halt retinopathy will be a welcoming sign for diabetic patients.
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Affiliation(s)
- Renu A Kowluru
- Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA
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34
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Wachal Z, Szilágyi A, Takács B, Szabó AM, Priksz D, Bombicz M, Szilvássy J, Juhász B, Szilvássy Z, Varga B. Improved Survival and Retinal Function of Aging ZDF Rats in Long-Term, Uncontrolled Diabetes by BGP-15 Treatment. Front Pharmacol 2021; 12:650207. [PMID: 33935754 PMCID: PMC8085539 DOI: 10.3389/fphar.2021.650207] [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: 01/06/2021] [Accepted: 03/02/2021] [Indexed: 11/13/2022] Open
Abstract
Retinal complications of diabetes often lead to deterioration or even loss of vision. This hastens discovery of pharmacological agents able to counterbalance diabetic retinopathy. BGP-15, an emerging small molecule agent, was formerly proven by our workgroup to be retinoprotective on nonobese diabetic animals, Goto-Kakizaki rats. In the present study, we aimed to examine its long-term tolerability or incidental side effects on obese-prone Zucker diabetic fatty (ZDF) rats to further increase the rationale for a future human translation. To make terminal visual status comparable with our other investigations, we also carried out electroretinography (ERG) at the end of the experiment. Our study was started on 16-week-old ZDF rats and lasted for 52 weeks, while BGP was administered daily by gavage. During the 12 months of treatment, 100% of BGP-treated animals survived compared to the non-treated ZDF group, where 60% of the animals died, which was a statistically significant difference. Based on ERG results, BGP-15 was able to counterbalance visual deterioration of ZDF rats caused by long-term diabetes. Some moderate but significant changes were seen in OGTT results and some relationship to oxidative stress by the western blot method: BGP-15 was able to increase expression of HSP70 and decrease that of NFkB in eyes of rats. These were in concert with our previous observations of SIRT1 increment and MMP9 decrement in diabetic eyes by BGP. In summary, not only is BGP-15 not harmful in the long run but it is even able to reduce the related mortality and the serious consequences of diabetes. BGP-15 is an excellent candidate for future drug development against diabetic retinopathy.
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Affiliation(s)
- Zita Wachal
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Anna Szilágyi
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Barbara Takács
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Adrienn Mónika Szabó
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Dániel Priksz
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Mariann Bombicz
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Judit Szilvássy
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Béla Juhász
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Zoltán Szilvássy
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Balázs Varga
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
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35
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Yang J, Miao X, Yang FJ, Cao JF, Liu X, Fu JL, Su GF. Therapeutic potential of curcumin in diabetic retinopathy (Review). Int J Mol Med 2021; 47:75. [PMID: 33693955 PMCID: PMC7949626 DOI: 10.3892/ijmm.2021.4908] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinopathy (DR) is a type of retinal microangiopathy caused by diabetes mellitus. It has become the leading cause of blindness among working individuals worldwide. DR is becoming increasingly common among younger diabetic patients and there is a need for lifelong treatment. The pathogenic mechanisms of DR are influenced by a number of factors, such as hyperglycemia, hyperlipidemia, inflammatory response and oxidative stress, among others. Currently, the treatment methods for DR mainly include retinal photocoagulation, vitrectomy, or anti‑vascular endothelial growth factor (VEGF) therapy. However, these methods have some disadvantages and limitations. Therefore, it is a matter of great interest and urgency to discover drugs that can target the pathogenesis of DR. Since ancient times, traditional Chinese medicine practitioners have accumulated extensive experiences in the use of Chinese herbal medicine for the prevention and treatment of diseases. In the theory of traditional Chinese medicine, curcumin has the effects of promoting blood circulation and relieving pain. A number of studies have also demonstrated that curcumin has multiple biological activities, including exerting anti‑apoptotic, anti‑inflammatory, antioxidant and antitumor properties. In recent years, studies have also confirmed that curcumin can prevent a variety of diabetic complications, including diabetic nephropathy (DN). However, the preventive and curative effects of curcumin on DR and its mechanisms of action have not yet been fully elucidated. The present review aimed to explore the therapeutic potential of curcumin in diabetes mellitus and DR.
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Affiliation(s)
- Jian Yang
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xiao Miao
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Feng-Juan Yang
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jin-Feng Cao
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xin Liu
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jin-Ling Fu
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Guan-Fang Su
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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36
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Rao H, Jalali JA, Johnston TP, Koulen P. Emerging Roles of Dyslipidemia and Hyperglycemia in Diabetic Retinopathy: Molecular Mechanisms and Clinical Perspectives. Front Endocrinol (Lausanne) 2021; 12:620045. [PMID: 33828528 PMCID: PMC8020813 DOI: 10.3389/fendo.2021.620045] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/25/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetic retinopathy (DR) is a significant cause of vision loss and a research subject that is constantly being explored for new mechanisms of damage and potential therapeutic options. There are many mechanisms and pathways that provide numerous options for therapeutic interventions to halt disease progression. The purpose of the present literature review is to explore both basic science research and clinical research for proposed mechanisms of damage in diabetic retinopathy to understand the role of triglyceride and cholesterol dysmetabolism in DR progression. This review delineates mechanisms of damage secondary to triglyceride and cholesterol dysmetabolism vs. mechanisms secondary to diabetes to add clarity to the pathogenesis behind each proposed mechanism. We then analyze mechanisms utilized by both triglyceride and cholesterol dysmetabolism and diabetes to elucidate the synergistic, additive, and common mechanisms of damage in diabetic retinopathy. Gathering this research adds clarity to the role dyslipidemia has in DR and an evaluation of the current peer-reviewed basic science and clinical evidence provides a basis to discern new potential therapeutic targets.
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Affiliation(s)
- Hussain Rao
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
| | - Jonathan A. Jalali
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
| | - Thomas P. Johnston
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri – Kansas City, Kansas City, MO, United States
| | - Peter Koulen
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
- Department of Biomedical Sciences, School of Medicine, University of Missouri – Kansas City, Kansas City, MO, United States
- *Correspondence: Peter Koulen,
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37
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Sun YN, Liu B, Wang JJ, Li XM, Zhu JY, Liu C, Yao J, Zhong YL, Jiang Q, Yan B. Identification of aberrantly expressed circular RNAs in hyperlipidemia-induced retinal vascular dysfunction in mice. Genomics 2020; 113:593-600. [PMID: 32991963 DOI: 10.1016/j.ygeno.2020.09.055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/07/2020] [Accepted: 09/23/2020] [Indexed: 10/23/2022]
Abstract
Hyperlipidemia-induced retinal vascular dysfunction is a complex pathological process. circRNAs are important regulators of biological processes and disease progression. However, the expression pattern of circRNAs in hyperlipidemia-induced retinal vascular dysfunction remains unclear. Herein, we used a murine model of hyperlipidemia and identified 317 differentially expressed circRNAs between hyperlipidemic retinas and normolipidemic retinas by circRNA microarrays. GO analysis indicated that the host genes of dysregulated circRNAs were targeted to cell differentiation (ontology: biological process), cytoplasm (ontology: cellular component), and protein binding (ontology: molecular function). Pathway analysis revealed that circRNAs-mediated network was mostly enriched in focal adhesion signaling. Notably, circLDB1 was significantly up-regulated in the serum of coronary artery disease patients and aqueous humor of age-related macular degeneration patients. circLDB1 regulated endothelial cell viability, proliferation, and apoptosis in vitro. Thus, circRNAs are the promising targets for the prediction and diagnosis of hyperlipidemia-induced vascular diseases.
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Affiliation(s)
- Ya-Nan Sun
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Ban Liu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jia-Jian Wang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Xiu-Miao Li
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Jun-Ya Zhu
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Chang Liu
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Jin Yao
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yu-Ling Zhong
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Qin Jiang
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
| | - Biao Yan
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.
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38
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Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease. Antioxidants (Basel) 2020; 9:antiox9100905. [PMID: 32977483 PMCID: PMC7598160 DOI: 10.3390/antiox9100905] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease.
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Kowluru RA, Mohammad G. Epigenetics and Mitochondrial Stability in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy. Sci Rep 2020; 10:6655. [PMID: 32313015 PMCID: PMC7171070 DOI: 10.1038/s41598-020-63527-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 03/20/2020] [Indexed: 02/07/2023] Open
Abstract
Retinopathy continues to progress even when diabetic patients try to control their blood sugar, but the molecular mechanism of this 'metabolic memory' phenomenon remains elusive. Retinal mitochondria remain damaged and vicious cycle of free radicals continues to self-propagate. DNA methylation suppresses gene expression, and diabetes activates DNA methylation machinery. Our aim was to investigate the role of DNA methylation in continued compromised mitochondrial dynamics and genomic stability in diabetic retinopathy. Using retinal endothelial cells, incubated in 20 mM glucose for four days, followed by 5 mM glucose for four days, and retinal microvessels from streptozotocin-induced diabetic rats in poor glycemia for four months, followed by normal glycemia for four additional months, DNA methylation of mitochondrial fusion and mismatch repair proteins, Mfn2 and Mlh1 respectively, was determined. Retinopathy was detected in trypsin-digested microvasculature. Re-institution of good glycemia had no beneficial effect on hypermethylation of Mfn2 and Mlh1 and retinal function (electroretinogram), and the retinopathy continued to progress. However, intervention of good glycemia directly with DNA methylation inhibitors (Azacytidine or Dnmt1-siRNA), prevented Mfn2 and Mlh1 hypermethylation, and ameliorated retinal dysfunction and diabetic retinopathy. Thus, direct regulation of DNA methylation can prevent/reverse diabetic retinopathy by maintaining mitochondrial dynamics and DNA stability, and prevent retinal functional damage.
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MESH Headings
- Animals
- Azacitidine/pharmacology
- Cell Line
- DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
- DNA (Cytosine-5-)-Methyltransferase 1/genetics
- DNA (Cytosine-5-)-Methyltransferase 1/metabolism
- DNA Methylation
- DNA, Mitochondrial/genetics
- DNA, Mitochondrial/metabolism
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Experimental/therapy
- Diabetic Retinopathy/chemically induced
- Diabetic Retinopathy/genetics
- Diabetic Retinopathy/pathology
- Diabetic Retinopathy/therapy
- Disease Progression
- Electroretinography
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Epigenesis, Genetic
- GTP Phosphohydrolases/genetics
- GTP Phosphohydrolases/metabolism
- Glucose/adverse effects
- Humans
- Hyperglycemia/chemically induced
- Hyperglycemia/genetics
- Hyperglycemia/pathology
- Hyperglycemia/therapy
- Male
- Mitochondria/drug effects
- Mitochondria/genetics
- Mitochondria/metabolism
- Mitochondria/pathology
- MutL Protein Homolog 1/genetics
- MutL Protein Homolog 1/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Rats
- Rats, Wistar
- Retina/drug effects
- Retina/metabolism
- Retina/pathology
- Signal Transduction
- Streptozocin/administration & dosage
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Affiliation(s)
- Renu A Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA.
| | - Ghulam Mohammad
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA
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40
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Kowluru RA. Retinopathy in a Diet-Induced Type 2 Diabetic Rat Model and Role of Epigenetic Modifications. Diabetes 2020; 69:689-698. [PMID: 31949005 PMCID: PMC7085254 DOI: 10.2337/db19-1009] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 01/08/2020] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes accounts for 90% of the population with diabetes, and these patients are generally obese and hyperlipidemic. In addition to hyperglycemia, hyperlipidemia is also closely related with diabetic retinopathy. The aim was to investigate retinopathy in a model closely mimicking the normal progression and metabolic features of the population with type 2 diabetes and elucidate the molecular mechanism. Retinopathy was evaluated in rats fed a 45% kcal as fat diet for 8 weeks before administering streptozotocin, 30 mg/kg body weight (T2D), and compared with age- and duration-matched type 1 diabetic rats (T1D) (60 mg/kg streptozotocin). The role of epigenetic modifications in mitochondrial damage was evaluated in retinal microvasculature. T2D rats were obese and severely hyperlipidemic, with impaired glucose and insulin tolerance compared with age-matched T1D rats. While at 4 months of diabetes, T1D rats had no detectable retinopathy, T2D rats had significant retinopathy, their mitochondrial copy numbers were lower, and mtDNA and Rac1 promoter DNA methylation was exacerbated. At 6 months, retinopathy was comparable in T2D and T1D rats, suggesting that obesity exaggerates hyperglycemia-induced epigenetic modifications, accelerating mitochondrial damage and diabetic retinopathy. Thus, maintenance of good lifestyle and BMI could be beneficial in regulating epigenetic modifications and preventing/retarding retinopathy in patients with diabetes.
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MESH Headings
- Animals
- DNA Methylation
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 2/etiology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetic Retinopathy/genetics
- Diabetic Retinopathy/metabolism
- Diet, High-Fat/adverse effects
- Disease Models, Animal
- Epigenesis, Genetic
- Insulin Resistance/physiology
- Male
- Promoter Regions, Genetic
- Rats
- Rats, Sprague-Dawley
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Affiliation(s)
- Renu A Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI
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41
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Bettadahalli S, Acharya P, Talahalli R. Evidence on n-3 Fatty Acids and Oleic Acid Role in Retinal Inflammation and Microvascular Integrity: Insight from a Hyperlipidemic Rat Model. Inflammation 2020; 43:868-877. [DOI: 10.1007/s10753-019-01172-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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42
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Ji B, Wei H, Ding Y, Liang H, Yao L, Wang H, Qu H, Deng H. Protective potential of klotho protein on diabetic retinopathy: Evidence from clinical and in vitro studies. J Diabetes Investig 2020; 11:162-169. [PMID: 31197979 PMCID: PMC6944830 DOI: 10.1111/jdi.13100] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/18/2019] [Accepted: 06/11/2019] [Indexed: 01/14/2023] Open
Abstract
AIMS/INTRODUCTION The purpose of the present study was to observe the relationship between serum α-klotho (KL) protein level and diabetic retinopathy (DR), and to further examine the effects of KL protein on apoptosis induced by palmitic acid (PA) in human retinal endothelial cells. MATERIALS AND METHODS A total of 17 healthy people and 60 type 2 diabetes patients were included. According to the results from fundus fluorescein angiography, the diabetes patients were divided into three subgroups: without DR, non-proliferative DR and proliferative DR. Serum KL level was measured by enzyme-linked immunosorbent assay. In vitro, human retinal endothelial cells were exposed to PA with or without KL protein. Apoptosis rates were analyzed by flow cytometry analysis. Apoptotic-related protein expressions were detected by western blotting analysis. RESULTS Serum KL level was lower in diabetes patients than that in healthy participants (P = 0.007), and was gradually decreased among the without DR, non-proliferative DR and proliferative DR subgroups (P = 0.045). A logistic regression analysis showed that after adjusting for the other confounding factors, serum KL level was independently and negatively related with DR (P = 0.049). Furthermore, the increased apoptosis rates induced by PA were inhibited with the addition of KL protein. Consistently, KL protein reversed the expression levels of the increased pro-apoptotic protein Bax and the decreased anti-apoptotic protein Bcl-2 induced by PA. However, the anti-apoptotic effect of KL protein was attenuated by LY294002 through the phosphatidylinositol 3 kinase-serine∕threonine kinase pathway. CONCLUSIONS The data suggested that KL protein was probably a potential protective factor against retinopathy in type 2 diabetes patients.
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Affiliation(s)
- Baolan Ji
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Huili Wei
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Yao Ding
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Huimin Liang
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Lu Yao
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Hang Wang
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Hua Qu
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Huacong Deng
- Department of EndocrinologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
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43
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Mohammad G, Duraisamy AJ, Kowluru A, Kowluru RA. Functional Regulation of an Oxidative Stress Mediator, Rac1, in Diabetic Retinopathy. Mol Neurobiol 2019; 56:8643-8655. [PMID: 31300985 PMCID: PMC6842106 DOI: 10.1007/s12035-019-01696-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 07/03/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE Early activation of cytosolic NADPH oxidase-2 (Nox2) in diabetes increases retinal ROS production, damaging their mitochondria. The assembly of Nox2 holoenzyme requires activation of a small molecular weight G protein Rac1. Rac1 activation is regulated by guanine exchange factors and guanine nucleotide-dissociation inhibitors, and post-translational modifications assist in its association with exchange factors and dissociation inhibitors. The goal of this study is to investigate the mechanisms of Rac1 activation in the development of diabetic retinopathy. METHODS The levels of the dissociation inhibitor, prenylating enzyme (farnesyltransferase, FNTA), and exchange factor Vav2 were quantified in human retinal endothelial cells, incubated in normal or high glucose for 96 h. The roles of prenylation and Vav2 in Rac1-Nox2-ROS mitochondrial damage were confirmed in FNTA-siRNA-transfected cells and using the Vav2 inhibitor EHop, respectively. Retinal histopathology and functional changes associated with diabetic retinopathy were analyzed in diabetic mice receiving EHop for 6 months. Key parameters of Rac1 activation were confirmed in the retinal microvasculature from human donors with diabetic retinopathy. RESULTS In HRECs, glucose increased FNTA and Vav2 and decreased the dissociation inhibitor. FNTA-siRNA and EHop inhibited glucose-induced activation of Rac1-Nox2-ROS signaling. In diabetic mice, EHop ameliorated the development of retinopathy and functional/structural abnormalities and attenuated Rac1-Nox2-mitochondrial damage. Similar alterations in Rac1 regulators were observed in retinal microvasculature from human donors with diabetic retinopathy. In diabetes, Rac1 prenylation and its interactions with Vav2 contribute to Nox2-ROS-mitochondrial damage, and the pharmacological inhibitors to attenuate Rac1 interactions with its regulators could have the potential to halt/inhibit the development of diabetic retinopathy. Graphical Abstract Activation of prenylating enzyme farnesyltransferase (FNTA) in diabetes, prenylates Rac1. The binding of Rac1 with guanine nucleotide-dissociation inhibitor (GDI) is decreased, but its association with the guanine exchange factor, Vav2, is increased, resulting in Rac1 activation. Active Rac1 helps in the assembly of Nox2 holoenzyme, and Nox2 activation increases cytosolic ROS production, damaging the mitochondria. Damaged mitochondria accelerate capillary cell apoptosis, and ultimately, results in the development of diabetic retinopathy.
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Affiliation(s)
- Ghulam Mohammad
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, 4717 St. Antoine, Detroit, MI, 48201, USA
| | - Arul J Duraisamy
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, 4717 St. Antoine, Detroit, MI, 48201, USA
| | - Anjan Kowluru
- Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA
- John D. Dingell VA Medical Center, Detroit, MI, USA
| | - Renu A Kowluru
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, 4717 St. Antoine, Detroit, MI, 48201, USA.
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Allen RS, Feola A, Motz CT, Ottensmeyer AL, Chesler KC, Dunn R, Thulé PM, Pardue MT. Retinal Deficits Precede Cognitive and Motor Deficits in a Rat Model of Type II Diabetes. Invest Ophthalmol Vis Sci 2019; 60:123-133. [PMID: 30640976 DOI: 10.1167/iovs.18-25110] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To investigate the temporal appearance of retinal, cognitive, and motor deficits in Goto-Kakizaki (GK) rats, a spontaneously occurring, polygenic model of type II diabetes. GK rats develop impaired insulin secretion at 2 weeks and fasting hyperglycemia at 4 weeks. Methods In male and female GK rats and Wistar controls, glucose tolerance test (hyperglycemia) and electroretinogram (ERG, retinal function) were performed at 4 and 8 weeks of age. Spectral domain-optical coherence tomography (retinal structure) was assessed at 6 weeks. Spatial alternation (cognitive function) and number of entries (exploratory behavior) were assessed via Y-maze at 4, 5, 6, 7, and 8 weeks. Rotarod (motor function) was performed at 4, 6, and 8 weeks. Results By 4 weeks, the GK rats exhibited significant glucose intolerance (P < 0.001) and retinal deficits, including delays in ERG implicit times (flicker, P < 0.01; oscillatory potentials, P < 0.001). In addition, the GK rats showed greater ERG amplitudes (P < 0.001) and thinner retinas (P < 0.001). At 7 weeks, the GK rats showed deficits in cognitive function (P < 0.001) and exploratory behavior (P < 0.01). However, no motor function deficits were observed by 8 weeks. Interestingly, the male GK rats showed greater hyperglycemia (P < 0.05), but the female rats showed greater ERG delays (P < 0.001). Conclusions In GK rats, retinal function deficits developed prior to cognitive or motor deficits. Future studies will investigate common mechanistic links, long-term functional and vascular changes, and whether early retinal deficits can predict cognitive dysfunction or late-stage retinal disease.
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Affiliation(s)
- Rachael S Allen
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States.,Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States
| | - Andrew Feola
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States.,Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States
| | - Cara T Motz
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States
| | - Amy L Ottensmeyer
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States.,Department of Ophthalmology, Emory University, Atlanta, Georgia, United States
| | - Kyle C Chesler
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States.,Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States
| | - Ryan Dunn
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States.,Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States
| | - Peter M Thulé
- Section Endocrinology & Metabolism, Atlanta VA Health Care System & Emory University School of Medicine, Decatur, Georgia, United States
| | - Machelle T Pardue
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, Georgia, United States.,Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States
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45
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Mohammad HMF, Sami MM, Makary S, Toraih EA, Mohamed AO, El-Ghaiesh SH. Neuroprotective effect of levetiracetam in mouse diabetic retinopathy: Effect on glucose transporter-1 and GAP43 expression. Life Sci 2019; 232:116588. [PMID: 31226418 DOI: 10.1016/j.lfs.2019.116588] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 06/14/2019] [Accepted: 06/17/2019] [Indexed: 01/12/2023]
Abstract
AIMS Retinopathy is a neurodegenerative complication associating diabetes mellitus. Diabetic retinopathy (DR) is the primary reason of visual loss during early adulthood. DR has a complicated multifactorial pathophysiology initiated by hyperglycaemia-induced ischaemic neurodegenerative retinal changes, followed by vision-threatening consequences. The main therapeutic modalities for DR involve invasive delivery of intravitreal antiangiogenic agents as well as surgical interventions. The current work aimed to explore the potential anti-inflammatory and retinal neuroprotective effects of levetiracetam. MAIN METHODS This study was performed on alloxan-induced diabetes in mice (n: 21). After 10 weeks, a group of diabetic animals (n: 7) was treated with levetiracetam (25 mg/kg) for six weeks. Retinal tissues were dissected and paraffin-fixed for examination using (1) morphometric analysis with haematoxylin and eosin (HE), (2) immunohistochemistry (GLUT1, GFAP and GAP43), and (3) RT-PCR-detected expression of retinal inflammatory and apoptotic mediators (TNF-α, IL6, iNOS, NF-κB and Tp53). KEY FINDINGS Diabetic mice developed disorganized and debilitated retinal layers with upregulation of the gliosis marker GFAP and downregulation of the neuronal plasticity marker GAP43. Additionally, diabetic retinae showed increased transcription of NF-κB, TNF-α, IL6, iNOS and Tp53. Levetiracetam-treated mice showed downregulation of retinal GLUT1 with relief and regression of retinal inflammation and improved retinal structural organization. SIGNIFICANCE Levetiracetam may represent a potential neuroprotective agent in DR. The data presented herein supported an anti-inflammatory role of levetiracetam. However, further clinical studies may be warranted to confirm the effectiveness and safety of levetiracetam in DR patients.
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Affiliation(s)
- Hala M F Mohammad
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Central Lab., Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Manal M Sami
- Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Samy Makary
- Department of Medical Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Eman A Toraih
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt; Molecular Lab, Center of Excellence of Molecular and Cellular Medicine, Suez Canal University, Ismailia, Egypt
| | - Amany O Mohamed
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Sabah H El-Ghaiesh
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt; Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia.
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Duraisamy AJ, Mohammad G, Kowluru RA. Mitochondrial fusion and maintenance of mitochondrial homeostasis in diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1617-1626. [PMID: 30922813 DOI: 10.1016/j.bbadis.2019.03.013] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/11/2019] [Accepted: 03/22/2019] [Indexed: 01/01/2023]
Abstract
Mitochondria are dynamic in structure, and undergo continuous fusion-fission to maintain their homeostasis. In diabetes, retinal mitochondria are swollen, their membrane is damaged and mitochondrial fusion protein, mitofusin 2 (Mfn2), is decreased. DNA methylation machinery is also activated and methylation status of genes implicated in mitochondrial damage and biogenesis is altered. This study aims to investigate the role of mitochondrial fusion in the development of diabetic retinopathy, and to illustrate the molecular mechanism responsible for Mfn2 suppression. Using human retinal endothelial cells, manipulated for Mfn2, we investigated the role of fusion in mitochondrial structural and functional damage in diabetes. The molecular mechanism of its suppression in diabetic milieu was determined by investigating Mfn2 promoter DNA methylation, and confirmed using molecular and pharmacological inhibitors of DNA methylation. Similar studies were performed in the retinal microvasculature (prepared by hypotonic shock method) of diabetic rats, and human donors with documented diabetic retinopathy. Overexpression of Mfn2 prevented glucose-induced increase in mitochondrial fragmentation, decrease in complex III activity and increase in membrane permeability, mtDNA damage and apoptosis. High glucose hypermethylated Mfn2 promoter and decreased transcription factor (SP1) binding, and Dnmt inhibition protected Mfn2 promoter from these changes. In streptozotocin-induced diabetic rats, intravitreal administration of Dnmt1-siRNA attenuated Mfn2 promoter hypermethylation and restored its expression. Human donors with diabetic retinopathy confirmed Mfn2 promoter DNA hypermethylation. Thus, regulating Mfn2 and its epigenetic modifications by molecular/pharmacological means will protect mitochondrial homeostasis in diabetes, and could attenuate the development of retinopathy in diabetic patients.
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MESH Headings
- Adult
- Aged
- Animals
- Cell Line
- DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
- DNA (Cytosine-5-)-Methyltransferase 1/genetics
- DNA (Cytosine-5-)-Methyltransferase 1/metabolism
- DNA Methylation
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diabetic Retinopathy/genetics
- Diabetic Retinopathy/metabolism
- Diabetic Retinopathy/pathology
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Epigenesis, Genetic
- GTP Phosphohydrolases/genetics
- GTP Phosphohydrolases/metabolism
- Homeostasis/genetics
- Humans
- Male
- Middle Aged
- Mitochondria/genetics
- Mitochondria/metabolism
- Mitochondria/pathology
- Mitochondrial Dynamics
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism
- Promoter Regions, Genetic
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Rats
- Rats, Wistar
- Retina/metabolism
- Retina/pathology
- Signal Transduction
- Sp1 Transcription Factor/genetics
- Sp1 Transcription Factor/metabolism
- Streptozocin/administration & dosage
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Affiliation(s)
- Arul J Duraisamy
- Kresge Eye Institute, Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University, Detroit, MI, United States of America
| | - Ghulam Mohammad
- Kresge Eye Institute, Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University, Detroit, MI, United States of America
| | - Renu A Kowluru
- Kresge Eye Institute, Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University, Detroit, MI, United States of America.
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Elevated serum OxLDL is associated with progression of type 2 Diabetes Mellitus to diabetic retinopathy. Exp Eye Res 2019; 186:107668. [PMID: 31100308 DOI: 10.1016/j.exer.2019.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 03/30/2019] [Accepted: 05/13/2019] [Indexed: 12/11/2022]
Abstract
Hyperlipidemia is associated with the progression of diabetic retinopathy (DR). Paraoxonase 1 (PON1), an esterase is known to prevent systemic LDL oxidation. This study assessed if serum oxLDL is associated with the progression of Type 2 DM to DR. This study is part of a three-year hospital based prospective study where 87 subjects were recruited. This included T2DM without DR (n = 22); Non-Proliferative (NPDR) (n = 21) and Proliferative DR (PDR) (n = 22) along with age/sex matched controls (n = 22). Serum oxLDL-Ab was estimated by ELISA. Serum PON esterase activity and plasma Malondialdehyde (MDA) level were estimated by spectrophotometry and the serum Advanced Glycation End products (AGE) level by spectroflourimetry. The systemic levels of oxLDL, AGE and MDA were increased with the progression of T2DM without DR to DR as seen by ANOVA (P < 0.05). Serum oxLDL-Ab levels showed a positive correlation to total cholesterol (P = 0.04) as evaluated in the DR group. Statin intake was found to lower PON esterase activity (P < 0.05). Based on this pilot study, it is proposed that elevated serum oxLDL should be validated in larger cohort studies to ensure it could be potential risk factor for the progression of T2DM to DR.
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Mishra M, Duraisamy AJ, Bhattacharjee S, Kowluru RA. Adaptor Protein p66Shc: A Link Between Cytosolic and Mitochondrial Dysfunction in the Development of Diabetic Retinopathy. Antioxid Redox Signal 2019; 30:1621-1634. [PMID: 30105917 PMCID: PMC6459280 DOI: 10.1089/ars.2018.7542] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
AIMS Diabetes increases oxidative stress in the retina and dysfunctions their mitochondria, accelerating capillary cell apoptosis. A 66 kDa adaptor protein, p66Shc, is considered as a sensor of oxidative stress-induced apoptosis. In the pathogenesis of diabetic retinopathy, a progressive disease, reactive oxygen species (ROS) production by activation of a small molecular weight G-protein (Ras-related C3 botulinum toxin substrate 1 [Rac1])-Nox2 signaling precedes mitochondrial damage. Rac1 activation is facilitated by guanine exchange factors (GEFs), and p66Shc increases Rac1-specific GEF activity of Son of Sevenless 1 (Sos1). p66Shc also possesses oxidoreductase activity and can directly stimulate mitochondrial ROS generation. Our aim was to investigate the role of p66Shc in the development of diabetic retinopathy and mechanism of its transcription. RESULTS High glucose increased p66Shc expression in human retinal endothelial cells, and elevated acetylated histone 3 lysine 9 (H3K9) levels and transcriptional factor p53 binding at its promoter. Glucose also augmented interactions between Rac1 and Sos1 and activated Rac1-Nox2. Phosphorylation of p66Shc was increased, allowing it to interact with peptidyl prolyl isomerase to facilitate its localization inside the mitochondria, culminating in mitochondrial damage. P66shc-small interfering RNA (siRNA) inhibited glucose-induced Rac1 activation and mitochondrial damage. Similar results are observed in retinal microvessels from diabetic rats. INNOVATION This is the first report identifying the role of p66Shc in the development of diabetic retinopathy and implicating increased histone acetylation in its transcriptional regulation. CONCLUSION Thus, p66Shc has dual role in the development of diabetic retinopathy; its regulation in the early stages of the disease should impede Rac1-ROS production and, in the later stages, prevent mitochondrial damage and initiation of a futile cycle of free radicals.
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Affiliation(s)
- Manish Mishra
- 1 Department of Ophthalmology, Kresge Eye Institute, Wayne State University, Detroit, Michigan
| | - Arul J Duraisamy
- 1 Department of Ophthalmology, Kresge Eye Institute, Wayne State University, Detroit, Michigan
| | - Sudarshan Bhattacharjee
- 1 Department of Ophthalmology, Kresge Eye Institute, Wayne State University, Detroit, Michigan
| | - Renu A Kowluru
- 1 Department of Ophthalmology, Kresge Eye Institute, Wayne State University, Detroit, Michigan.,2 Department of Anatomy/Cell Biology, Kresge Eye Institute, Wayne State University, Detroit, Michigan
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Salvianolic Acid B Attenuates Apoptosis of HUVEC Cells Treated with High Glucose or High Fat via Sirt1 Activation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:9846325. [PMID: 31118974 PMCID: PMC6500650 DOI: 10.1155/2019/9846325] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 02/13/2019] [Accepted: 04/07/2019] [Indexed: 11/17/2022]
Abstract
High glucose and high fat are important inducements for the development and progression of diabetic cardiopathy. Salvianolic acid B (SAB), which is the most abundant and bioactive compound in Danshen, attenuates oxidative stress-related disorders, such as cardiovascular diseases, cerebral ischemia, and diabetes. However, the effect of SAB on diabetic cardiopathy is not clear. The aim of study was to investigate the effect and the underlying molecular mechanisms of SAB on diabetic cardiopathy in vitro model. The human umbilical vein endothelial (HUVEC) cells were treated with high glucose (HG, 30 mM) or high fat (palmitic acid, PA, 0.75 mM) in the presence or absence of SAB (100, 200, and 400 mg/L) and incubated for 24 h. We found that HG or PA induced apoptosis of HUVEC cells, while treatment with SAB inhibited the apoptosis. We also found that SAB reversed HG- or PA-induced oxidative stress, apoptosis cell cytokines production, and expression of thioredoxin-interacting protein (TXNIP). Moreover, SAB increased HG- or PA-induced expression of Sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide- (NAD+-) dependent histone deacetylase. Exposure of HUVEC cells to Ex527 (Sirt1 inhibitor) suppressed the effect of SAB on acetyl-p53 and procaspase-3 expressions. In conclusion, the results suggested that SAB could attenuate HUVEC cells damage treated with HG or PA via Sirt1 and might be a potential therapy agent for the diabetic cardiopathy treatment.
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50
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Qaddoumi M, Al-Khamis Y, Channanath A, Tuomilehto J, Badawi D. The Status of Metabolic Control in Patients With Type 2 Diabetes Attending Dasman Diabetes Institute, Kuwait. Front Endocrinol (Lausanne) 2019; 10:412. [PMID: 31297092 PMCID: PMC6607397 DOI: 10.3389/fendo.2019.00412] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/07/2019] [Indexed: 01/22/2023] Open
Abstract
Purpose: To evaluate metabolic control in patients with type 2 diabetes at Dasman Diabetes Institute (DDI, Kuwait), a specialist diabetes clinic and research center, and to investigate its association with patient demographics and clinical characteristics. Methods: Data from 963 patients with type 2 diabetes were retrospectively collected from the Knowledge Based Health Records maintained at DDI for patients who attended DDI during 2011-2014. The collected data included patient demographics, clinical characteristics, and anti-diabetic medications. Student's t-test was used to evaluate the differences in mean values between poor and good glycemic control groups. Categorical variables were assessed using chi-square analysis with Fisher's exact test for small data sets. Results: The patients' mean age was 53.0 ± 9.5 years with equal number of males and females. Females (34.4 ± 7.2 kg/m2) had a higher mean body mass index than males (32.1 ± 6.4 kg/m2). The mean fasting blood glucose and HbA1c levels were 9.6 ± 3.8 mmol/L and 8.5 ± 1.8%, respectively. Dyslipidemia (46%) and hypertension (40%) were the most common comorbidities, whereas nephropathy (36%) and neuropathy (35%) were the most common diabetic complications. The most commonly used anti-diabetic medication was metformin (55%). Factors significantly associated with poor glycemic control (HbA1c level ≥ 7%) included insulin use; neuropathy or foot ulcers as diabetic complications; and elevated systolic blood pressure and total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose levels. Factors significantly associated with good glycemic control included metformin use and elevated high-density lipoprotein cholesterol level. The proportion of patients with good glycemic control (HbA1c level < 7%) was 29.5%. A large proportion of the patients with poor glycemic control were only administered monotherapy drugs, and two-thirds of the patients were obese. Further, the American Diabetes Association (ADA) recommendations for blood pressure and LDL cholesterol level were met (62 and 63%, respectively) by follow-up year 4. Conclusion: The therapeutic management of type 2 diabetes in Kuwait is suboptimal. Therapeutic strategies should ensure better adherence to ADA guidelines, evaluate the high obesity rates, and adherence to lifestyle recommendations by patients, and continually promote diabetes education and self-empowerment.
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Affiliation(s)
- Mohammad Qaddoumi
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
- *Correspondence: Mohammad Qaddoumi ;
| | | | | | - Jaakko Tuomilehto
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Center for Vascular Prevention, Danube-University Krems, Krems an der Donau, Austria
- Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
| | - Dalia Badawi
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Dalia Badawi ;
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