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Chen Z, Chen R, Wang J, Zhu L, Niu J, Li M, Wu K, Mo J, Zheng S, Liu B, Zhou P, Lan T. Ligusticum cycloprolactam ameliorates hyperuricemic nephropathy through inhibition of TLR4/NF-κB signaling. J Nutr Biochem 2025; 139:109864. [PMID: 39952622 DOI: 10.1016/j.jnutbio.2025.109864] [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: 07/31/2024] [Revised: 01/21/2025] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
Hyperuricemia is a metabolic disease attributed to a sustained dysregulation of purine metabolism, manifesting as consistently elevated blood uric acid levels. Hyperuricemic nephropathy (HN) is a renal complication of hyperuricemia. It is characterized by the deposition of urate crystals, inflammatory cell infiltration and tubulointerstitial injury. Ligusticum cycloprolactam (LIGc) is a novel monomeric derivative of the active ingredient ligustilide (LIG) from Angelica sinensis (Oliv.). LIG demonstrates anti-inflammatory and antioxidant properties. Nevertheless, the therapeutic potential of LIGc to ameliorate HN required further investigation. Our study revealed that LIGc effectively reduced serum uric acid and attenuated HN in mice induced by co-administering potassium oxonate and hypoxanthine. Our research demonstrated that LIGc treatment improved renal function in mice with HN by regulating the expression of uric acid transporters. Histopathological analysis showed that LIGc treatment reduced tubular damage, inflammatory infiltration and interstitial collagen deposition. Mechanistically, LIGc alleviated renal injury by inhibiting the TLR4/NF-κB signaling pathway both in vivo and in vitro. Our study revealed that LIGc effectively mitigated HN by attenuating the inflammatory response through the TLR4/NF-κB signaling pathway, providing new perspectives for the treatment of HN.
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Affiliation(s)
- Zhe Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Rong Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Jiamin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Lin Zhu
- Department of Pediatric Nephrology and Rheumatology, Sichuan Provincial Maternity and Child Health Care Hospital, Sichuan Clinical Research Center for pediatric nephrology, Chengdu, Sichuan, China
| | - Jie Niu
- Department of Pediatric Nephrology and Rheumatology, Sichuan Provincial Maternity and Child Health Care Hospital, Sichuan Clinical Research Center for pediatric nephrology, Chengdu, Sichuan, China
| | - Minghui Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Kaireng Wu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Juxian Mo
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Siqi Zheng
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Bing Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Ping Zhou
- Department of Pediatric Nephrology and Rheumatology, Sichuan Provincial Maternity and Child Health Care Hospital, Sichuan Clinical Research Center for pediatric nephrology, Chengdu, Sichuan, China.
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China; College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China.
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Liu J, Chen K, Tang M, Mu Q, Zhang S, Li J, Liao J, Jiang X, Wang C. Oxidative stress and inflammation mediate the adverse effects of cadmium exposure on all-cause and cause-specific mortality in patients with diabetes and prediabetes. Cardiovasc Diabetol 2025; 24:145. [PMID: 40158078 PMCID: PMC11954339 DOI: 10.1186/s12933-025-02698-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND The effect of cadmium exposure on mortality risk among individuals with diabetes and prediabetes remains unclear, particularly regarding potential mediation by oxidative stress and inflammation. This study aimed to investigate the associations of blood cadmium levels with all-cause, cardiovascular disease (CVD), and cancer mortality and the mediating effects of oxidative stress and inflammation biomarkers in patients with diabetes and prediabetes. METHODS In this prospective cohort study, we analyzed 17,687 adults with diabetes and prediabetes from the National Health and Nutrition Examination Survey (NHANES, 1999-2018). Nine biomarkers related to oxidative stress (gamma-glutamyl transferase [GGT], uric acid [UA], high-density lipoprotein [HDL], UA to HDL ratio [UHR]) and inflammation (neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], neutrophil-monocyte-lymphocyte ratio [NMLR], systemic inflammation response index [SIRI], systemic immune-inflammation index [SII]) were systematically assessed. Kaplan-Meier survival analysis, Cox proportional hazards models, and restricted cubic splines (RCS) were applied to evaluate the association of cadmium with mortality risk. Generalized linear models were used to assess the association of cadmium with oxidative stress and inflammation biomarkers, while Cox regression and RCS evaluated their effects on mortality. Causal mediation analysis identified biological pathways mediated by oxidative stress and inflammation. Stratified and sensitivity analyses were further employed to confirm the robustness of the results. RESULTS During 161,047.75 person-years of follow-up, 3562 deaths occurred, including 1214 from CVD and 680 from cancer. Higher blood cadmium levels were associated with increased risks of all-cause mortality (fully adjusted hazard ratio [HR]: 2.17; 95% confidence interval [CI] 1.69-2.79, comparing highest vs. lowest quartile), CVD mortality (HR 2.06; 95% CI 1.41-3.02), and cancer mortality (HR 2.38; 95% CI 1.47-3.85), without evidence of nonlinear relationship. Mediation analyses indicated that UA, NLR, MLR, NMLR, and SIRI partially mediated the associations of cadmium with all-cause and CVD mortality, although the mediated proportions were relatively modest (ranging from 1.4 to 4.8%). Additionally, GGT mediated a small fraction of the associations with all-cause and cancer mortality. CONCLUSION Cadmium exposure increases the risk of all-cause, CVD, and cancer mortality in patients with diabetes and prediabetes. Oxidative stress and inflammation appear to partially mediate this adverse effect. These findings emphasize the urgent need for targeted interventions to reduce cadmium-related mortality risks. RESEARCH INSIGHTS What is currently known about this topic? Cadmium exposure is linked to increased mortality. Oxidative stress and inflammation are critical in diabetes development and complications. What is the key research question? Does cadmium exposure increase mortality risk in patients with diabetes and prediabetes? Are oxidative stress and inflammation involved in mediating these effects? What is new? Cadmium exposure increases all-cause and cause-specific mortality in diabetes and prediabetes. Oxidative stress and inflammation mediate these associations. How might this study influence clinical practice? Monitor cadmium, oxidative stress, and inflammation to reduce mortality in diabetes and prediabetes.
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Affiliation(s)
- Jingqi Liu
- Department of Public Health Laboratory Sciences, West China School of Public Health, West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Kehan Chen
- Department of Public Health Laboratory Sciences, West China School of Public Health, West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Mingyuan Tang
- Department of Public Health Laboratory Sciences, West China School of Public Health, West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Qunzheng Mu
- Department of Public Health Laboratory Sciences, West China School of Public Health, West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Shirong Zhang
- Department of Public Health Laboratory Sciences, West China School of Public Health, West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Jiayuan Li
- Department of Epidemiology and Health Statistics, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiaqiang Liao
- Department of Epidemiology and Health Statistics, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xia Jiang
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chuan Wang
- Department of Public Health Laboratory Sciences, West China School of Public Health, West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, Sichuan, China.
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Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol 2024; 98:1323-1367. [PMID: 38483584 PMCID: PMC11303474 DOI: 10.1007/s00204-024-03696-4] [Citation(s) in RCA: 198] [Impact Index Per Article: 198.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 01/31/2024] [Indexed: 03/27/2024]
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized for playing a dual role, since they can be either deleterious or beneficial to biological systems. An imbalance between ROS production and elimination is termed oxidative stress, a critical factor and common denominator of many chronic diseases such as cancer, cardiovascular diseases, metabolic diseases, neurological disorders (Alzheimer's and Parkinson's diseases), and other disorders. To counteract the harmful effects of ROS, organisms have evolved a complex, three-line antioxidant defense system. The first-line defense mechanism is the most efficient and involves antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). This line of defense plays an irreplaceable role in the dismutation of superoxide radicals (O2•-) and hydrogen peroxide (H2O2). The removal of superoxide radicals by SOD prevents the formation of the much more damaging peroxynitrite ONOO- (O2•- + NO• → ONOO-) and maintains the physiologically relevant level of nitric oxide (NO•), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., β-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine The Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Suliman Y Alomar
- Doping Research Chair, Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Saleh H Alwasel
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
- Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
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Saha S, Sachivkina N, Karamyan A, Novikova E, Chubenko T. Advances in Nrf2 Signaling Pathway by Targeted Nanostructured-Based Drug Delivery Systems. Biomedicines 2024; 12:403. [PMID: 38398005 PMCID: PMC10887079 DOI: 10.3390/biomedicines12020403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Nanotechnology has gained significant interest in various applications, including sensors and therapeutic agents for targeted disease sites. Several pathological consequences, including cancer, Alzheimer's disease, autoimmune diseases, and many others, are mostly driven by inflammation and Nrf2, and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), plays a crucial role in maintaining redox status, the expression of antioxidant genes, and the inflammatory response. Interestingly, tuning the Nrf2/antioxidant response element (ARE) system can affect immune-metabolic mechanisms. Although many phytochemicals and synthetic drugs exhibited potential therapeutic activities, poor aqueous solubility, low bioavailability, poor tissue penetration, and, consequently, poor specific drug targeting, limit their practical use in clinical applications. Also, the therapeutic use of Nrf2 modulators is hampered in clinical applications by the absence of efficient formulation techniques. Therefore, we should explore the engineering of nanotechnology to modulate the inflammatory response via the Nrf2 signaling pathway. This review will initially examine the role of the Nrf2 signaling pathway in inflammation and oxidative stress-related pathologies. Subsequently, we will also review how custom-designed nanoscale materials encapsulating the Nrf2 activators can interact with biological systems and how this interaction can impact the Nrf2 signaling pathway and its potential outcomes, emphasizing inflammation.
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Affiliation(s)
- Sarmistha Saha
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura 281406, India
| | - Nadezhda Sachivkina
- Department of Microbiology V.S. Kiktenko, Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia;
| | - Arfenya Karamyan
- Department of Veterinary Medicine, Agrarian Technological Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.K.); (E.N.); (T.C.)
| | - Ekaterina Novikova
- Department of Veterinary Medicine, Agrarian Technological Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.K.); (E.N.); (T.C.)
| | - Tamara Chubenko
- Department of Veterinary Medicine, Agrarian Technological Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.K.); (E.N.); (T.C.)
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Ali F, Alom S, Ali SR, Kondoli B, Sadhu P, Borah C, Kakoti BB, Ghosh SK, Shakya A, Ahmed AB, Singh UP, Bhat HR. Ebselen: A Review on its Synthesis, Derivatives, Anticancer Efficacy and Utility in Combating SARS-COV-2. Mini Rev Med Chem 2024; 24:1203-1225. [PMID: 37711004 DOI: 10.2174/1389557523666230914103339] [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: 02/09/2023] [Revised: 05/26/2023] [Accepted: 06/16/2023] [Indexed: 09/16/2023]
Abstract
Ebselen is a selenoorganic chiral compound with antioxidant properties comparable to glutathione peroxidase. It is also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one. In studies examining its numerous pharmacological activities, including antioxidant, anticancer, antiviral, and anti- Alzheimer's, ebselen has demonstrated promising results. This review's primary objective was to emphasize the numerous synthesis pathways of ebselen and their efficacy in fighting cancer. The data were collected from multiple sources, including Scopus, PubMed, Google Scholar, Web of Science, and Publons. The starting reagents for the synthesis of ebselen are 2-aminobenzoic acid and N-phenyl benzamide. It was discovered that ebselen has the ability to initiate apoptosis in malignant cells and prevent the formation of new cancer cells by scavenging free radicals. In addition, ebselen increases tumor cell susceptibility to apoptosis by inhibiting TNF-α mediated NF-kB activation. Ebselen can inhibit both doxorubicin and daunorubicin-induced cardiotoxicity. Allopurinol and ebselen administered orally can be used to suppress renal ototoxicity and nephrotoxicity. Due to excessive administration, diclofenac can induce malignancy of the gastrointestinal tract, which ebselen can effectively suppress. Recent research has demonstrated ebselen to inhibit viral function by binding to cysteinecontaining catalytic domains of various viral proteases. It was discovered that ebselen could inhibit the catalytic dyad function of Mpro by forming an irreversible covalent bond between Se and Cys145, thereby altering protease function and inhibiting SARS-CoV-2. Ebselen may also inhibit the activation of endosomal NADPH oxidase of vascular endothelial cells, which is believed to be required for thrombotic complications in COVID-19. In this review, we have included various studies conducted on the anticancer effect of ebselen as well as its inhibition of SARS-CoV-2.
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Affiliation(s)
- Farak Ali
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
- Girijananda Chowdhury Institute of Pharmaceutical Science, Tezpur Medical College and Hospital, Tezpur, Sonitpur Assam, 784501,India
| | - Shahnaz Alom
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
- Girijananda Chowdhury Institute of Pharmaceutical Science, Tezpur Medical College and Hospital, Tezpur, Sonitpur Assam, 784501,India
| | - Sheikh Rezzak Ali
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
| | - Biswanarayan Kondoli
- Department of Pharmacy, Tripura University, Suryamani Nagar, Agartala, Tripura 799022, India
| | - Prativa Sadhu
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
| | - Chinmoyee Borah
- Girijananda Chowdhury Institute of Pharmaceutical Science, Guwahati, Kamrup, Assam, 781017, India
| | - Bibhuti Bushan Kakoti
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
| | - Surajit Kumar Ghosh
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
| | - Anshul Shakya
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
| | - Abdul Baquee Ahmed
- Girijananda Chowdhury Institute of Pharmaceutical Science,Tezpur Medical College and Hospital, Tezpur, Sonitpur-784501, Assam, India
| | - Udaya Pratap Singh
- Drug Design & Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh, 211007, India
| | - Hans Raj Bhat
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India
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Zou Z, Ren T, Li Y, Zeng Q, Wang X, Teng J, Xu J, Jia P, Ding X. The Association Between Serum Glutathione Peroxidase-3 Concentration and Risk of Acute Kidney Injury After Cardiac Surgery: A Nested Case-Control Study. Am J Cardiol 2023; 209:29-35. [PMID: 37839462 DOI: 10.1016/j.amjcard.2023.08.141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/20/2023] [Accepted: 08/20/2023] [Indexed: 10/17/2023]
Abstract
Oxidative stress has an integral role in the pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI). Glutathione peroxidase 3 (GPx3) is an important antioxidant enzyme in circulation and is mainly secreted by the kidney. This study aimed to evaluate the relation between GPx3 protein and CSA-AKI. This study is a nested case-control study in Zhongshan Hospital affiliated with Fudan University. We examined serum samples from 80 CSA-AKI patients and 80 age- and gender-matched non-AKI patients who underwent cardiac surgery. AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) 2012 criteria. We measured serum GPx3 concentration using the enzyme-linked immunosorbent assay. GPx3 ratio is the ratio of preoperative and 6 hours postoperative of GPx3 protein concentration. We applied dose-response relation analyses to odds ratio in different GPx3 ratio levels and integrated it into the logistic model to predict the risk of AKI. The receiver operating characteristic curve and area under the curve (AUC) was used to assess the prediction models. Postoperative serum GPx3 concentrations were significantly lower in the AKI group compared with the non-AKI group (1.78 ± 0.33 vs 2.03 ± 0.27, p <0.001). Malondialdehyde was higher in the AKI than in the non-AKI group (17.74 ± 8.65 vs 7.48 ± 4.59, p <0.001). The AKI risk increased in a dose-dependent manner, which was flat in the first half of the GPx3 ratio and then tended to be faster. The peaking odds ratio of CSA-AKI was 2.615 at the GPx3 ratio of 1.21 to 1.40. The AUC value to predict CSA-AKI only included the GPx3 ratio was 72.3%. After gradually integrating other covariates (body mass index, aortic crossclamp time, and cardiopulmonary bypass), the model showed an AUC of 82.6%. The serum GPx3 concentration was significantly lower in the CSA-AKI group. GPx3 ratio has a good predictive value for CSA-AKI, which may be a potential early diagnostic marker for AKI.
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Affiliation(s)
- Zhouping Zou
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Ting Ren
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Yang Li
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Qi Zeng
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Xiaoyan Wang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Jie Teng
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China; Nephrology Clinical Quality Control Center of Xiamen, Xiamen, China
| | - Jiarui Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
| | - Ping Jia
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China; Nephrology Clinical Quality Control Center of Xiamen, Xiamen, China.
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Rybarczyk A, Formanowicz D, Formanowicz P. Key Therapeutic Targets to Treat Hyperglycemia-Induced Atherosclerosis Analyzed Using a Petri Net-Based Model. Metabolites 2023; 13:1191. [PMID: 38132873 PMCID: PMC10744714 DOI: 10.3390/metabo13121191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 11/29/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
Chronic superphysiological glucose concentration is a hallmark of diabetes mellitus (DM) and a cause of damage to many types of cells. Atherosclerosis coexists with glucose metabolism disturbances, constituting a significant problem and exacerbating its complications. Atherosclerosis in DM is accelerated, so it is vital to slow its progression. However, from the complex network of interdependencies, molecules, and processes involved, choosing which ones should be inhibited without blocking the pathways crucial for the organism's functioning is challenging. To conduct this type of analysis, in silicotesting comes in handy. In our study, to identify sites in the network that need to be blocked to have an inhibitory effect on atherosclerosis in hyperglycemia, which is toxic for the human organism, we created a model using Petri net theory and performed analyses. We have found that blocking isoforms of protein kinase C (PKC)-PKCβ and PKCγ-in diabetic patients can contribute to the inhibition of atherosclerosis progression. In addition, we have discovered that aldose reductase inhibition can slow down atherosclerosis progression, and this has been shown to reduce PKC (β and γ) expression in DM. It has also been observed that diminishing oxidative stress through the inhibitory effect on the AGE-RAGE axis may be a promising therapeutic approach in treating hyperglycemia-induced atherosclerosis. Moreover, the blockade of NADPH oxidase, the key enzyme responsible for the formation of reactive oxygen species (ROS) in blood vessels, only moderately slowed down atherosclerosis development. However, unlike aldose reductase blockade, or direct PKC (β and γ), the increased production of mitochondrial ROS associated with mitochondrial dysfunction effectively stopped after NADPH oxidase blockade. The results obtained may constitute the basis for further in-depth research.
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Affiliation(s)
- Agnieszka Rybarczyk
- Institute of Computing Science, Poznan University of Technology, 60-695 Poznan, Poland;
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland
- Faculty of Electrical Engineering, Gdynia Maritime University, 81-225 Gdynia, Poland
| | - Dorota Formanowicz
- Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
| | - Piotr Formanowicz
- Institute of Computing Science, Poznan University of Technology, 60-695 Poznan, Poland;
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Yang CC, Peng CH, Huang LY, Chen FY, Kuo CH, Wu CZ, Hsia TL, Lin CY. Comparison between multiple logistic regression and machine learning methods in prediction of abnormal thallium scans in type 2 diabetes. World J Clin Cases 2023; 11:7951-7964. [DOI: 10.12998/wjcc.v11.i33.7951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/23/2023] [Accepted: 11/13/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND The prevalence of type 2 diabetes (T2D) has been increasing dramatically in recent decades, and 47.5% of T2D patients will die of cardiovascular disease. Thallium-201 myocardial perfusion scan (MPS) is a precise and non-invasive method to detect coronary artery disease (CAD). Most previous studies used traditional logistic regression (LGR) to evaluate the risks for abnormal CAD. Rapidly developing machine learning (Mach-L) techniques could potentially outperform LGR in capturing non-linear relationships.
AIM To aims were: (1) Compare the accuracy of Mach-L methods and LGR; and (2) Found the most important factors for abnormal TMPS.
METHODS 556 T2D were enrolled in the study (287 men and 269 women). Demographic and biochemistry data were used as independent variables and the sum of stressed score derived from MPS scan was the dependent variable. Subjects with a MPS score ≥ 9 were defined as abnormal. In addition to traditional LGR, classification and regression tree (CART), random forest, Naïve Bayes, and eXtreme gradient boosting were also applied. Sensitivity, specificity, accuracy and area under the receiver operation curve were used to evaluate the respective accuracy of LGR and Mach-L methods.
RESULTS Except for CART, the other Mach-L methods outperformed LGR, with gender, body mass index, age, low-density lipoprotein cholesterol, glycated hemoglobin and smoking emerging as the most important factors to predict abnormal MPS.
CONCLUSION Four Mach-L methods are found to outperform LGR in predicting abnormal TMPS in Chinese T2D, with the most important risk factors being gender, body mass index, age, low-density lipoprotein cholesterol, glycated hemoglobin and smoking.
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Affiliation(s)
- Chung-Chi Yang
- Division of Cardiovascular Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City 32551, Taiwan
- Division of Cardiovascular, Tri-service General Hospital, Taipei City 114202, Taiwan
| | - Chung-Hsin Peng
- Department of Urology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan
- School of Medicine, Fu-Jen Catholic University, New Taipei City 242062, Taiwan
| | - Li-Ying Huang
- Department of Internal Medicine, Department of Medical Education, School of Medicine, Fu Jen Catholic University Hospital, New Taipei City 243, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 243, Taiwan
| | - Fang Yu Chen
- Department of Endocrinology, Fu Jen Catholic University Hospital, New Taipei City 243, Taiwan
| | - Chun-Heng Kuo
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 243, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Fu Jen Catholic University Hospital, New Taipei City 243, Taiwan
| | - Chung-Ze Wu
- Division of Endocrinology, Shuang Ho Hospital, New Taipei City 23561, Taiwan
- School of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
| | - Te-Lin Hsia
- Department of Internal Medicine, Cardinal Tien Hospital, New Taipei City 23148, Taiwan
| | - Chung-Yu Lin
- Department of Cardiology, Fu Jen Catholic University Hospital, New Taipei City 24352, Taiwan
- Graduate Institute of Business Administration, Fu Jen Catholic University, New Taipei City 242062, Taiwan
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9
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Shaikh SA, Patel B, Priyadarsini IK, Vavilala SL. Combating planktonic and biofilm growth of Serratia marcescens by repurposing ebselen. Int Microbiol 2023; 26:693-704. [PMID: 36507979 DOI: 10.1007/s10123-022-00301-5] [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: 05/30/2022] [Revised: 10/21/2022] [Accepted: 11/17/2022] [Indexed: 12/14/2022]
Abstract
AIM OF THE STUDY The rising instances of multidrug-resistant pathogens are rapidly evolving into a global healthcare crisis. Identifying new ways of synthesis of antibiotics is both time-consuming and expensive. Repurposing existing drugs for the treatment of such antimicrobial-resistant pathogens has also been explored. METHODS AND RESULTS In the current study, ebselen was screened for antibacterial and antibiofilm activity against Serratia marcescens. Various antibacterial studies such as minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time-kill curves, intracellular reactive oxygen species (ROS) quantification, and colony-forming unit assays were performed. The antibiofilm potential was assayed by biofilm inhibition, cell surface hydrophobicity assay, eradication, quantification of extracellular DNA (eDNA), and extracellular polymeric substance (EPS) layer and scanning electron microscopy (SEM) analysis were performed. Anti-quorum sensing assay was validated by quantifying the virulence factors production. Further molecular docking of ebselen with two quorum sensing (QS) specific proteins was also carried out. Antibacterial susceptibility tests showed potent antimicrobial activity of ebselen against S. marcescens with MIC50 of 14 μg/mL. Ebselen's ability to disturb the redox environment by inducing significant ROS generation led to bacterial death. It also showed concentration-dependent bactericidal activity as indicated by reduced bacterial growth and colony-forming unit propagation. Ebselen was also found to prevent biofilm attachment by altering the cell surface hydrophobicity while also being effective against preformed biofilms as validated by scanning electron microscopy (SEM) analysis. Additionally, ebselen showed reduced virulence factors like urease enzyme activity and prodigiosin pigment production indicating its promising anti-quorum sensing potential. Molecular docking analysis validated the strong binding of ebselen with QS-specific proteins (1Joe and PigG) with binding energies of - 6.6 and - 8.1kj/mol through hydrogen bonds and aromatic interactions. These results show that ebselen has potent antibiofilm potential that can be explored to identify treatment against bacterial infections.
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Affiliation(s)
- Shaukat Ali Shaikh
- School of Chemical Sciences, UM DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina Campus, Mumbai, India
| | - Bharti Patel
- School of Biological Sciences, UM DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina Campus, Mumbai, India
| | - Indira K Priyadarsini
- School of Chemical Sciences, UM DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina Campus, Mumbai, India.
| | - Sirisha L Vavilala
- School of Biological Sciences, UM DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina Campus, Mumbai, India.
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10
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Baylis RA, Gao H, Wang F, Bell CF, Luo L, Björkegren JL, Leeper NJ. Identifying shared transcriptional risk patterns between atherosclerosis and cancer. iScience 2023; 26:107513. [PMID: 37636064 PMCID: PMC10448075 DOI: 10.1016/j.isci.2023.107513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/18/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Cancer and cardiovascular disease (CVD) are the leading causes of death worldwide. Numerous overlapping pathophysiologic mechanisms have been hypothesized to drive the development of both diseases. Further investigation of these common pathways could allow for the identification of mutually detrimental processes and therapeutic targeting to derive mutual benefit. In this study, we intersect transcriptomic datasets correlated with disease severity or patient outcomes for both cancer and atherosclerotic CVD. These analyses confirmed numerous pathways known to underlie both diseases, such as inflammation and hypoxia, but also identified several novel shared pathways. We used these to explore common translational targets by applying the drug prediction software, OCTAD, to identify compounds that simultaneously reverse the gene expression signature for both diseases. These analyses suggest that certain tumor-specific therapeutic approaches may be implemented so that they avoid cardiovascular consequences, and in some cases may even be used to simultaneously target co-prevalent cancer and atherosclerosis.
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Affiliation(s)
- Richard A. Baylis
- Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco, CA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Hua Gao
- Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford, CA, USA
| | - Fudi Wang
- Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford, CA, USA
| | - Caitlin F. Bell
- Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Lingfeng Luo
- Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford, CA, USA
| | - Johan L.M. Björkegren
- Department of Medicine, Karolinska Institute, Huddinge, Sweden
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nicholas J. Leeper
- Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
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11
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Li Y, Wang L, Zhang J, Xu B, Zhan H. Integrated multi-omics and bioinformatic methods to reveal the mechanisms of sinomenine against diabetic nephropathy. BMC Complement Med Ther 2023; 23:287. [PMID: 37580684 PMCID: PMC10424381 DOI: 10.1186/s12906-023-04119-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/05/2023] [Indexed: 08/16/2023] Open
Abstract
OBJECTIVES Diabetic Nephropathy (DN) is a serious complication of diabetes, the diagnosis and treatment of DN is still limited. Sinomenine (SIN) is an active extract of herbal medicine and has been applied into the therapy of DN. METHODS In the part of bioinformatic analyses, network pharmacology and molecular docking analyses were conducted to predict the important pathway of SIN treatment for DN. In-vivo study, DN rats were randomized to be treated with vehicle or SIN (20 mg/kg or 40 mg/kg) daily by gavage for 8 weeks. Then, the pharmacological effect of SIN on DN and the potential mechanisms were also evaluated by 24 h albuminuria, histopathological examination, transcriptomics, and metabolomics. RESULTS Firstly, network pharmacology and molecular docking were performed to show that SIN might improve DN via AGEs/RAGE, IL-17, JAK, TNF pathways. Urine biochemical parameters showed that SIN treatment could significantly reduce 24 h albuminuria of DN rats. Transcriptomics analysis found SIN could affect DN progression via inflammation and EMT pathways. Metabolic pathway analysis found SIN would mainly involve in arginine biosynthesis, linoleic acid metabolism, arachidonic acid metabolism, and glycerophospholipid metabolism to affect DN development. CONCLUSIONS We confirmed that SIN could inhibit the progression of DN via affecting multiple genes and metabolites related pathways.
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Affiliation(s)
- Yan Li
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, 117892, Fujian, China
- Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen, 361000, XM, China
- Xiamen Key Laboratory of Rheumatology and Clinical Immunology, Xiamen University, Xiamen, 12466, Fujian, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China
| | - Lei Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Jimin Zhang
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, 117892, Fujian, China
- Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen, 361000, XM, China
- Xiamen Key Laboratory of Rheumatology and Clinical Immunology, Xiamen University, Xiamen, 12466, Fujian, China
| | - Bojun Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China.
| | - Huakui Zhan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China.
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12
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He H, Han Q, Wang S, Long M, Zhang M, Li Y, Zhang Y, Gu N. Design of a Multifunctional Nanozyme for Resolving the Proinflammatory Plaque Microenvironment and Attenuating Atherosclerosis. ACS NANO 2023; 17:14555-14571. [PMID: 37350440 DOI: 10.1021/acsnano.3c01420] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/24/2023]
Abstract
Persistent inflammation within atherosclerotic plaques is a crucial factor contributing to plaque vulnerability and rupture. It has become increasingly evident that the proinflammatory microenvironment of the plaque, characterized by heightened monocyte recruitment, oxidative stress, and impaired clearance of apoptotic cells, plays a significant role in perpetuating inflammation and impeding its resolution. Consequently, targeting and eliminating these proinflammatory features within the plaque microenvironment have emerged as a promising therapeutic approach to restore inflammation resolution and mitigate the progression of atherosclerosis. While recent advancements in nanotherapeutics have demonstrated promising results in targeting individual proinflammatory characteristics, the development of an effective therapeutic strategy capable of simultaneously addressing multiple proinflammatory features remains a challenge. In this study, we developed a multifunctional nanozyme based on Prussian blue, termed PBNZ@PP-Man, to simultaneously target and eliminate various proinflammatory factors within the plaque microenvironment. Through systematic investigations, we have elucidated the antiatherosclerotic mechanisms of PBNZ@PP-Man. Our results demonstrate that PBNZ@PP-Man possesses the ability to accumulate within atherosclerotic plaques and effectively eliminate multiple proinflammatory factors, leading to inflammation resolution. Specifically, PBNZ@PP-Man suppresses monocyte recruitment, scavenges reactive oxygen species, and enhances efferocytosis. Notably, PBNZ@PP-Man exhibits a much stronger efficacy to resolve the proinflammatory plaque microenvironment and attenuate atherosclerosis in comparison to the approach that merely eliminates one single risky factor in the plaque. It significantly enhances the inflammation resolution capabilities of macrophages and attenuates atherosclerosis. These results collectively underscore the importance of modulating the proinflammatory plaque microenvironment as a complementary strategy for resolving inflammation in atherosclerosis.
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Affiliation(s)
- Hongliang He
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Qinggong Han
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Shi Wang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Mengmeng Long
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Miao Zhang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Yan Li
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Yu Zhang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China
| | - Ning Gu
- School of Medicine, Nanjing University, Nanjing 210093, People's Republic of China
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13
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Thabet NM, Abdel-Rafei MK, Amin MM. Fractionated whole body γ-irradiation aggravates arthritic severity via boosting NLRP3 and RANKL expression in adjuvant-induced arthritis model: the mitigative potential of ebselen. Inflammopharmacology 2023:10.1007/s10787-023-01238-5. [PMID: 37131046 DOI: 10.1007/s10787-023-01238-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 04/16/2023] [Indexed: 05/04/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease associated with oxidative stress that causes excruciating pain, discomfort, and joint destruction. Ebselen (EB), a synthesized versatile organo-selenium compound, protects cells from reactive oxygen species (ROS)-induced injury by mimicking glutathione peroxidase (GPx) action. This study aimed to investigate the antioxidant and anti-inflammatory effects of EB in an arthritic irradiated model. This goal was achieved by subjecting adjuvant-induced arthritis (AIA) rats to fractionated whole body γ-irradiation (2 Gy/fraction once per week for 3 consecutive weeks, for a total dose of 6 Gy) and treating them with EB (20 mg/kg/day, p.o) or methotrexate (MTX; 0.05 mg/kg; twice/week, i.p) as a reference anti-RA drug. The arthritic clinical signs, oxidative stress and antioxidant biomarkers, inflammatory response, expression of NOD-like receptor protein-3 (NLRP-3) inflammasome, receptor activator of nuclear factor κB ligand (RANKL), nuclear factor-κB (NF-κB), apoptotic indicators (caspase 1 and caspase 3), cartilage integrity marker (collagen-II), and histopathological examination of ankle joints were assessed. EB notably improved the severity of arthritic clinical signs, alleviated joint histopathological lesions, modulated oxidative stress and inflammation in serum and synovium, as well as reduced NLRP-3, RANKL, and caspase3 expression while boosting collagen-II expression in the ankle joints of arthritic and arthritic irradiated rats with comparable potency to MTX. Our findings suggest that EB, through its antioxidant and anti-inflammatory properties, has anti-arthritic and radioprotective properties in an arthritic irradiated model.
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Affiliation(s)
- Noura M Thabet
- Radiation Biology Department, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, 3 Ahmed El-Zomor Street, Nasr City, P.O. Box 29, Cairo, 11787, Egypt.
| | - Mohamed K Abdel-Rafei
- Radiation Biology Department, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, 3 Ahmed El-Zomor Street, Nasr City, P.O. Box 29, Cairo, 11787, Egypt.
| | - Mohamed M Amin
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Egypt
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14
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Huang Z, Chen G, Wu H, Huang X, Xu R, Deng F, Li Y. Ebselen restores peri-implantitis-induced osteogenic inhibition via suppressing BMSCs ferroptosis. Exp Cell Res 2023; 427:113612. [PMID: 37116735 DOI: 10.1016/j.yexcr.2023.113612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/12/2023] [Accepted: 04/21/2023] [Indexed: 04/30/2023]
Abstract
It is hard to reconstruct bone defects in peri-implantitis due to osteogenesis inhibited by excessive ROS. Ferroptosis, a recently identified regulated cell death characterized by iron- and reactive oxygen species- (ROS-) dependent lipid peroxidation, provides us with a new explanation. Our study aims to explore whether ferroptosis is involved in peri-implantitis-inhibited osteogenesis and confirm ebselen, an antioxidant with glutathione peroxidase (GPx)-like activity, could inhibit ferroptosis and promote osteogenesis in peri-implantitis. In this study, we used LPS to mimic the microenvironment of peri-implantitis. The osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) was assessed by alkaline phosphatase (ALP), Alizarin Red S, and mRNA and protein expression of osteogenic-related markers. Ferroptosis index analysis included iron metabolism, ROS production, lipid peroxidation and mitochondrial morphological changes. Iron overload, reduced antioxidant capability, excessive ROS, lipid peroxidation and the characteristic mitochondrial morphological changes of ferroptosis were observed in LPS-treated BMSCs, and adding Ferrostatin-1 (Fer-1) restored the inhibitory effect of ferroptosis on osteogenic differentiation of BMSCs. Furthermore, ebselen ameliorated LPS-induced ferroptosis and osteogenic inhibition, which was reversed by erastin. Our results demonstrated that ferroptosis is involved in osteogenic inhibition in peri-implantitis and ebselen could attenuate osteogenic dysfunction of BMSCs via inhibiting ferroptosis.
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Affiliation(s)
- Ziqing Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China
| | - Guanhui Chen
- Department of Stomatology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Hiokuan Wu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China
| | - Xiaoqiong Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China
| | - Ruogu Xu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China
| | - Feilong Deng
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China.
| | - Yiming Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China.
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15
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Argaev-Frenkel L, Rosenzweig T. Redox Balance in Type 2 Diabetes: Therapeutic Potential and the Challenge of Antioxidant-Based Therapy. Antioxidants (Basel) 2023; 12:antiox12050994. [PMID: 37237860 DOI: 10.3390/antiox12050994] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Oxidative stress is an important factor in the development of type 2 diabetes (T2D) and associated complications. Unfortunately, most clinical studies have failed to provide sufficient evidence regarding the benefits of antioxidants (AOXs) in treating this disease. Based on the known complexity of reactive oxygen species (ROS) functions in both the physiology and pathophysiology of glucose homeostasis, it is suggested that inappropriate dosing leads to the failure of AOXs in T2D treatment. To support this hypothesis, the role of oxidative stress in the pathophysiology of T2D is described, together with a summary of the evidence for the failure of AOXs in the management of diabetes. A comparison of preclinical and clinical studies indicates that suboptimal dosing of AOXs might explain the lack of benefits of AOXs. Conversely, the possibility that glycemic control might be adversely affected by excess AOXs is also considered, based on the role of ROS in insulin signaling. We suggest that AOX therapy should be given in a personalized manner according to the need, which is the presence and severity of oxidative stress. With the development of gold-standard biomarkers for oxidative stress, optimization of AOX therapy may be achieved to maximize the therapeutic potential of these agents.
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Affiliation(s)
| | - Tovit Rosenzweig
- Department of Molecular Biology, Ariel University, Ariel 4070000, Israel
- Adison School of Medicine, Ariel University, Ariel 4070000, Israel
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16
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Chen HC, Hou HY, Sung JM, Shieh CC. Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation. Front Med (Lausanne) 2023; 10:1097671. [PMID: 36993800 PMCID: PMC10040743 DOI: 10.3389/fmed.2023.1097671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/17/2023] [Indexed: 03/16/2023] Open
Abstract
BackgroundsCisplatin is a commonly used chemotherapeutic agent in cancer treatment. However, its high nephrotoxicity limits its therapeutic application and efficacy. Cisplatin induces nephrotoxicity mainly through oxidative stress and inflammation. Reactive oxygen species (ROS) in the kidneys mainly arise from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 2 (NOX2), which is highly upregulated during ischemia-reperfusion injury and diabetes mellitus. However, its role in cisplatin-induced acute kidney injury (AKI) remains unknown.MethodsA 8-10-week-old NOX2 gene-knockout and wild-type mice were injected with 25 mg/kg cisplatin intraperitoneally for experiments.ResultsWe investigated the role of NOX2 in cisplatin-induced AKI and found that NOX2-mediated ROS production is a key inflammatory mediator of proximal tubular cell injury in cisplatin-induced AKI. NOX2 gene-knockout alleviated cisplatin-induced renal function decline, tubular injury score, kidney injury molecule-1(Kim-1) expression, and interleukin (IL)-6 and IL-1α levels with a reduction of ROS production. Moreover, in cisplatin-induced AKI, intercellular adhesion molecule 1 (ICAM-1) and the chemoattractant CXC ligand 1 (CXCL1) were highly expressed in association with neutrophil infiltration, which were all attenuated by deletion of NOX2.ConclusionThese data indicate that NOX2 aggravates cisplatin nephrotoxicity by promoting ROS-mediated tissue injury and neutrophil infiltration. Thus, appropriate targeting of NOX2/ROS pathway may minimize the risk of cisplatin-induced kidney injury in patients receiving cancer therapy.
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Affiliation(s)
- Ho-Ching Chen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Renal Division, Department of Internal Medicine, Cishan Hospital, Ministry of Health and Welfare, Kaohsiung, Taiwan
| | - Hsin-Yu Hou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Junne-Ming Sung
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Renal Division, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
- *Correspondence: Junne-Ming Sung,
| | - Chi-Chang Shieh
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan
- Chi-Chang Shieh,
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Wu TW, Chou CL, Cheng CF, Lu SX, Wu YJ, Wang LY. Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study. Cardiovasc Diabetol 2023; 22:51. [PMID: 36894991 PMCID: PMC9999522 DOI: 10.1186/s12933-023-01787-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/01/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA). METHODS We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10-16, as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors. RESULTS Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10-7) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10-5), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects. CONCLUSIONS We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis.
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Affiliation(s)
- Tzu-Wei Wu
- Department of Medicine, MacKay Medical College, No. 46, Sec. 3, Zhongzheng Road, Sanzhi District, New Taipei City, Taiwan
| | - Chao-Liang Chou
- Department of Medicine, MacKay Medical College, No. 46, Sec. 3, Zhongzheng Road, Sanzhi District, New Taipei City, Taiwan.,Department of Neurology, MacKay Memorial Hospital, New Taipei City, Taiwan
| | - Chun-Fang Cheng
- Tamsui Health Station, Department of Health, New Taipei City Government, New Taipei City, Taiwan
| | - Shu-Xin Lu
- Department of Neurology, MacKay Memorial Hospital, New Taipei City, Taiwan
| | - Yih-Jer Wu
- Department of Medicine, MacKay Medical College, No. 46, Sec. 3, Zhongzheng Road, Sanzhi District, New Taipei City, Taiwan. .,Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan. .,Cardiovascular Center, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan. .,Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
| | - Li-Yu Wang
- Department of Medicine, MacKay Medical College, No. 46, Sec. 3, Zhongzheng Road, Sanzhi District, New Taipei City, Taiwan.
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Structure, Activation, and Regulation of NOX2: At the Crossroad between the Innate Immunity and Oxidative Stress-Mediated Pathologies. Antioxidants (Basel) 2023; 12:antiox12020429. [PMID: 36829988 PMCID: PMC9952346 DOI: 10.3390/antiox12020429] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/04/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multisubunit enzyme complex that participates in the generation of superoxide or hydrogen peroxide (H2O2) and plays a key role in several biological functions. Among seven known NOX isoforms, NOX2 was the first identified in phagocytes but is also expressed in several other cell types including endothelial cells, platelets, microglia, neurons, and muscle cells. NOX2 has been assigned multiple roles in regulating many aspects of innate and adaptive immunity, and human and mouse models of NOX2 genetic deletion highlighted this key role. On the other side, NOX2 hyperactivation is involved in the pathogenesis of several diseases with different etiologies but all are characterized by an increase in oxidative stress and inflammatory process. From this point of view, the modulation of NOX2 represents an important therapeutic strategy aimed at reducing the damage associated with its hyperactivation. Although pharmacological strategies to selectively modulate NOX2 are implemented thanks to new biotechnologies, this field of research remains to be explored. Therefore, in this review, we analyzed the role of NOX2 at the crossroads between immunity and pathologies mediated by its hyperactivation. We described (1) the mechanisms of activation and regulation, (2) human, mouse, and cellular models studied to understand the role of NOX2 as an enzyme of innate immunity, (3) some of the pathologies associated with its hyperactivation, and (4) the inhibitory strategies, with reference to the most recent discoveries.
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May L, Bartolo B, Harrison D, Guzik T, Drummond G, Figtree G, Ritchie R, Rye KA, de Haan J. Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery. Clin Sci (Lond) 2022; 136:1731-1758. [PMID: 36459456 PMCID: PMC9727216 DOI: 10.1042/cs20210862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/21/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death worldwide. An ongoing challenge remains the development of novel pharmacotherapies to treat CVD, particularly atherosclerosis. Effective mechanism-informed development and translation of new drugs requires a deep understanding of the known and currently unknown biological mechanisms underpinning atherosclerosis, accompanied by optimization of traditional drug discovery approaches. Current animal models do not precisely recapitulate the pathobiology underpinning human CVD. Accordingly, a fundamental limitation in early-stage drug discovery has been the lack of consensus regarding an appropriate experimental in vivo model that can mimic human atherosclerosis. However, when coupled with a clear understanding of the specific advantages and limitations of the model employed, preclinical animal models remain a crucial component for evaluating pharmacological interventions. Within this perspective, we will provide an overview of the mechanisms and modalities of atherosclerotic drugs, including those in the preclinical and early clinical development stage. Additionally, we highlight recent preclinical models that have improved our understanding of atherosclerosis and associated clinical consequences and propose model adaptations to facilitate the development of new and effective treatments.
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Affiliation(s)
- Lauren T. May
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | | | - David G. Harrison
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A
| | - Tomasz Guzik
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, U.K
- Department of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Grant R. Drummond
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria, Australia
| | - Gemma A. Figtree
- Kolling Research Institute, University of Sydney, Sydney, Australia
- Imaging and Phenotyping Laboratory, Charles Perkins Centre and Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Rebecca H. Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Kerry-Anne Rye
- Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia
| | - Judy B. de Haan
- Cardiovascular Inflammation and Redox Biology Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia
- Department Cardiometabolic Health, University of Melbourne, Parkville, Victoria 3010, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia
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20
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Li YX, Lu YP, Tang D, Hu B, Zhang ZY, Wu HW, Fan LJ, Cai KW, Tang C, Zhang YQ, Hong L, Dong JJ, Guan BZ, Yin LH, Dai Y, Bai WB, Zheng ZH, Zhu T. Anthocyanin improves kidney function in diabetic kidney disease by regulating amino acid metabolism. J Transl Med 2022; 20:510. [PMID: 36335368 PMCID: PMC9636632 DOI: 10.1186/s12967-022-03717-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Background Diabetic kidney disease (DKD) is among the most important causes for chronic kidney disease. Anthocyanins (ANT) are polyphenolic compounds present in various food and play an important role in ameliorating hyperglycemia and insulin sensitivity. However, the effects of ANT in DKD are still poorly understood. This study aimed to investigate the effect of ANT (cyanidin-3-O-glucoside [C3G]) on the renal function of DKD, and whether the anti-DKD effect of ANT is related to metabolic pathways. Methods To explore the role of ANT in DKD, we performed the examination of blood glucose, renal function, and histopathology. As for the mechanism, we designed the label-free quantification proteomics and nontargeted metabolomics analysis for kidney and serum. Subsequently, we revealed the anti-DKD effect of ANT through the bioinformatic analysis. Results We showed that the fasting blood glucose level (− 6.1 mmol/L, P = 0.037), perimeter of glomerular lesions (− 24.1 μm, P = 0.030), fibrosis score of glomerular (− 8.8%, P = 0.002), and kidney function (Cystatin C: − 701.4 pg/mL, P = 0.043; urine creatinine: − 701.4 mmol/L, P = 0.032) were significantly alleviated in DKD mice after ANT treatment compared to untreated in the 20th week. Further, proteins and metabolites in the kidneys of DKD mice were observed to be dramatically altered due to changes in amino acid metabolism with ANT treatment; mainly, taurine and hypotaurine metabolism pathway was upregulated (P = 0.0001, t value = 5.97). Furthermore, upregulated tryptophan metabolism (P < 0.0001, t value = 5.94) and tyrosine metabolism (P = 0.0037, t value = 2.91) pathways had effects on serum of DKD mice as responsed ANT regulating. Conclusions Our results suggested that prevention of the progression of DKD by ANT could be related to the regulation of amino acid metabolism. The use of dietary ANT may be one of the dietary strategies to prevent and treat DKD. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03717-9.
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21
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Liu Y, Wu Y, Jiang M. The emerging roles of PHOSPHO1 and its regulated phospholipid homeostasis in metabolic disorders. Front Physiol 2022; 13:935195. [PMID: 35957983 PMCID: PMC9360546 DOI: 10.3389/fphys.2022.935195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/07/2022] [Indexed: 11/25/2022] Open
Abstract
Emerging evidence suggests that phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1), a specific phosphoethanolamine and phosphocholine phosphatase, is involved in energy metabolism. In this review, we describe the structure and regulation of PHOSPHO1, as well as current knowledge about the role of PHOSPHO1 and its related phospholipid metabolites in regulating energy metabolism. We also examine mechanistic evidence of PHOSPHO1- and phospholipid-mediated regulation of mitochondrial and lipid droplets functions in the context of metabolic homeostasis, which could be potentially targeted for treating metabolic disorders.
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Affiliation(s)
- Yi Liu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yingting Wu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Mengxi Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- *Correspondence: Mengxi Jiang,
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22
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Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases. Antioxidants (Basel) 2022; 11:antiox11071408. [PMID: 35883899 PMCID: PMC9312358 DOI: 10.3390/antiox11071408] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/12/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system’s activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.
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Man B, Hu C, Yang G, Xiang J, Yang S, Ma C. Berberine attenuates diabetic atherosclerosis via enhancing the interplay between KLF16 and PPARα in ApoE−/− mice. Biochem Biophys Res Commun 2022; 624:59-67. [DOI: 10.1016/j.bbrc.2022.07.072] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 07/19/2022] [Indexed: 01/25/2023]
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Maiocchi S, Cartaya A, Thai S, Akerman A, Bahnson E. Antioxidant Response Activating nanoParticles (ARAPas) localize to atherosclerotic plaque and locally activate the Nrf2 pathway. Biomater Sci 2022; 10:1231-1247. [PMID: 35076645 PMCID: PMC9181183 DOI: 10.1039/d1bm01421h] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Atherosclerotic disease is the leading cause of death world-wide with few novel therapies available despite the ongoing health burden. Redox dysfunction is a well-established driver of atherosclerotic progression; however, the clinical translation of redox-based therapies is lacking. One of the challenges facing redox-based therapies is their targeted delivery to cellular domains of redox dysregulation. In the current study, we sought to develop Antioxidant Response Activating nanoParticles (ARAPas), encapsulating redox-based interventions, that exploit macrophage biology and the dysfunctional endothelium in order to selectively accumulate in atherosclerotic plaque. We employed flash nanoprecipitation (FNP) to synthesize bio-compatible polymeric nanoparticles encapsulating the hydrophobic Nrf2 activator drug, CDDO-Methyl (CDDOMe-ARAPas). Nuclear factor erythroid 2-related factor 2 (Nrf2)-activators are a promising class of redox-active drug molecules whereby activation of Nrf2 results in the expression of several antioxidant and cyto-protective enzymes that can be athero-protective. In this study, we characterize the physicochemical properties of CDDOMe-ARAPas as well as confirm their in vitro internalization by murine macrophages. Drug release of CDDOMe was determined by Nrf2-driven GFP fluorescence. Moreover, we show that these CDDOMe-ARAPas exert anti-inflammatory effects in classically activated macrophages. Finally, we show that CDDOMe-ARAPas selectively accumulate in atherosclerotic plaque of two widely-used murine models of atherosclerosis: ApoE-/- and LDLr-/- mice, and are capable of increasing gene expression of Nrf2-transcriptional targets in the atherosclerotic aortic arch. Future work will assess the therapeutic efficacy of intra-plaque Nrf2 activation with CDDOMe-ARAPas to inhibit atherosclerotic plaque progression. Overall, our present studies underline that targeting of atherosclerotic plaque is an effective means to enhance delivery of redox-based interventions.
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Affiliation(s)
- Sophie Maiocchi
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, NC 27599, USA. .,Curriculum of Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, NC 27599, USA.,Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, NC 27599, USA.,McAllister Heart Institute, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Ana Cartaya
- Center for Nanotechnology in Drug Delivery. University of North Carolina at Chapel Hill, NC 27599,McAllister Heart Institute. University of North Carolina at Chapel Hill, NC 27599.,Department of Pharmacology. University of North Carolina at Chapel Hill, NC 27599
| | - Sydney Thai
- Department of Surgery. University of North Carolina at Chapel Hill, NC 27599
| | - Adam Akerman
- Department of Surgery. University of North Carolina at Chapel Hill, NC 27599
| | - Edward Bahnson
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, NC 27599, USA. .,Curriculum of Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, NC 27599, USA.,Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, NC 27599, USA.,McAllister Heart Institute, University of North Carolina at Chapel Hill, NC 27599, USA.,Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA
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25
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Ahmad R, Chowdhury K, Kumar S, Irfan M, Reddy GS, Akter F, Jahan D, Haque M. Diabetes Mellitus: A Path to Amnesia, Personality, and Behavior Change. BIOLOGY 2022; 11:biology11030382. [PMID: 35336756 PMCID: PMC8945557 DOI: 10.3390/biology11030382] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary Diabetes Mellitus (DM) is a metabolic disorder resulting from a disturbance of insulin secretion, action, or both. Hyperglycemia and overproduction of superoxide induce the development and progression of chronic complications of DM. The impact of DM and its complication on the central nervous system (CNS) such as dementia and Alzheimer’s Disease (AD) still remain obscure. In dementia, there is a gradual decline in cognitive function. The incidence of dementia increases with age, and patient become socially, physically, and mentally more vulnerable and dependent. The symptoms often emerge decades after the onset of pathophysiology, thus impairing early therapeutic intervention. Most diabetic subjects who develop dementia are above the age of 65, but diabetes may also cause an increased risk of developing dementia before 65 years. Vascular dementia is the second most common form of dementia after AD. Type 2 DM (T2DM) increases the incidence of vascular dementia (since its covers the vascular system) and AD. The functional and structural integrity of the CNS is altered in T2DM due to increased synthesis of Aβ. Additionally, hyperphosphorylation of Tau protein also results from dysregulation of various signaling cascades in T2DM, thereby causing neuronal damage and AD. There is the prospect for development of a therapy that may help prevent or halt the progress of dementia resulting from T2DM. Abstract Type 2 diabetes mellitus is increasingly being associated with cognition dysfunction. Dementia, including vascular dementia and Alzheimer’s Disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear primarily in older patients. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes that affect the brain and lead to dementia development. The connection between diabetes mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted that mechanisms related to diabetes mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between Type 2 diabetes and dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s Disease and helping to explain the potential mechanisms behind the disease process. A Google search for “Diabetes Mellitus and Dementia” was carried out. Search was also done for “Diabetes Mellitus”, “Vascular Dementia”, and “Alzheimer’s Disease”. The literature search was done using Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the Type 2 diabetes’ effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding the different types of dementia and their relationship with diabetes.
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Affiliation(s)
- Rahnuma Ahmad
- Department of Physiology, Medical College for Women and Hospital, Dhaka 1230, Bangladesh;
| | - Kona Chowdhury
- Department of Pediatrics, Gonoshasthaya Samaj Vittik Medical College and Hospital, Dhaka 1344, Bangladesh;
| | - Santosh Kumar
- Department of Periodontology and Implantology, Karnavati School of Dentistry, Karnavati University, 907/A, Uvarsad Gandhinagar, Gujarat 382422, India;
| | - Mohammed Irfan
- Department of Forensics, Federal University of Pelotas, Pelotas 96020-010, RS, Brazil;
| | - Govindool Sharaschandra Reddy
- Department of Periodontics and Endodontics, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA;
| | - Farhana Akter
- Department of Endocrinology, Chittagong Medical College, Chattogram 4203, Bangladesh;
| | - Dilshad Jahan
- Department of Hematology, Asgar Ali Hospital, 111/1/A Distillery Road, Gandaria Beside Dhupkhola, Dhaka 1204, Bangladesh;
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur 57000, Malaysia
- Correspondence: or
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26
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Su X, Yu W, Liu A, Wang C, Li X, Gao J, Liu X, Jiang W, Yang Y, Lv S. San-Huang-Yi-Shen Capsule Ameliorates Diabetic Nephropathy in Rats Through Modulating the Gut Microbiota and Overall Metabolism. Front Pharmacol 2022; 12:808867. [PMID: 35058786 PMCID: PMC8764181 DOI: 10.3389/fphar.2021.808867] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic nephropathy (DN) in clinic. However, the mechanisms of SHYS on DN remain unknown. In this study, we used a high-fat diet (HFD) combined with streptozotocin (STZ) injection to establish a DN rat model. Next, we used 16S rRNA sequencing and untargeted metabolomics to study the potential mechanisms of SHYS on DN. Our results showed that SHYS treatment alleviated the body weight loss, hyperglycemia, proteinuria, pathological changes in kidney in DN rats. SHYS could also inhibite the oxidative stress and inflammatory response in kidney. 16S rRNA sequencing analysis showed that SHYS affected the beta diversity of gut microbiota community in DN model rats. SHYX could also decrease the Firmicutes to Bacteroidetes (F to B) ratio in phylum level. In genus level, SHYX treatment affected the relative abundances of Lactobacillus, Ruminococcaceae UCG-005, Allobaculum, Anaerovibrio, Bacteroides and Candidatus_Saccharimonas. Untargeted metabolomics analysis showed that SHYX treatment altered the serum metabolic profile in DN model rats through affecting the levels of guanidineacetic acid, L-kynurenine, prostaglandin F1α, threonine, creatine, acetylcholine and other 21 kind of metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, tryptophan metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, tyrosine metabolism, arginine and proline metabolism, arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and D-glutamine and D-glutamate metabolism pathways. Spearman correlation analysis showed that Lactobacillus, Candidatus_Saccharimonas, Ruminococcaceae UCG-005, Anaerovibrio, Bacteroides, and Christensenellaceae_R-7_group were closely correlated with most of physiological data and the differential metabolites following SHYS treatment. In conclusion, our study revealed multiple ameliorative effects of SHYS on DN including the alleviation of hyperglycemia and the improvement of renal function, pathological changes in kidney, oxidative stress, and the inflammatory response. The mechanism of SHYS on DN may be related to the improvement of gut microbiota which regulates arginine biosynthesis, TCA cycle, tyrosine metabolism, and arginine and proline metabolism.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Shuquan Lv
- Cangzhou Hospital of Integrated TCM and Western Medicine of Hebei Province, Cangzhou, China
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27
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The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus. Bioorg Chem 2021; 117:105455. [PMID: 34740055 PMCID: PMC8556866 DOI: 10.1016/j.bioorg.2021.105455] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/13/2021] [Accepted: 10/22/2021] [Indexed: 12/17/2022]
Abstract
The main protease (Mpro or 3CLpro) of
SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and
transcription, thus indicating a potential target for antiviral therapy.
A recent repurposing effort has identified ebselen, a multifunctional
drug candidate as an inhibitor of Mpro. Our docking of ebselen to the
binding pocket of Mpro crystal structure suggests a noncovalent
interaction for improvement of potency, antiviral activity and
selectivity. To test this hypothesis, we designed and synthesized ebselen
derivatives aimed at enhancing their non-covalent bonds within Mpro. The
inhibition of Mpro by ebselen derivatives (0.3 μM) was screened in both
HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger
inhibitory effect on Mpro with IC50 of
0.07–0.38 μM. Further evaluation of three derivatives showed that EB2-7
exhibited the most potent inhibition of SARS-CoV-2 viral replication with
an IC50 value of 4.08 µM in HPAepiC cells, as
compared to the prototype ebselen at 24.61 μM. Mechanistically, EB2-7
functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken
together, our identification of ebselen derivatives with improved
antiviral activity may lead to developmental potential for treatment of
COVID-19 and SARS-CoV-2 infection.
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28
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Wu TW, Chou CL, Cheng CF, Lu SX, Wang LY. Prevalences of diabetes mellitus and carotid atherosclerosis and their relationships in middle-aged adults and elders: a community-based study. J Formos Med Assoc 2021; 121:1133-1140. [PMID: 34674902 DOI: 10.1016/j.jfma.2021.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/31/2021] [Accepted: 10/04/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/PURPOSE Atherosclerosis and diabetes mellitus (DM) are both severe chronic diseases that cause huge burdens on patients' families and societies. Connections between the two diseases have brought high attention recently, however, population-based study with large sample size was few. The study aimed to explore the relationship between carotid atherosclerosis and DM. METHODS We enrolled 3908 adults aged 40-74 years from communities and measured their cardio-metabolic profiles and scanned their carotid arteries bilaterally. RESULTS The overall prevalence rates of carotid plaque and DM were 34.4 and 10.7%, respectively. The age-specific prevalence rates of DM and carotid plaque were nearly linearly correlated in both sexes (both Pearson's correlation coefficient r > 0.97). The prevalence rates of carotid plaque, total plaque number ≥3, maximum diameter stenosis ≥30%, and plaque score ≥3 were 53.6, 24.8, 19.1, and 28.6%, respectively, in DM patients and were 32.1, 9.4, 9.8, and 11.2%, respectively, in non-DM controls. After adjustment for other conventional risk factors, the multivariable-adjusted OR of having carotid plaque was 1.60 (95% CI 1.27-2.01) and were 2.06 (95% CI 1.55-2.75), 1.33 (95% CI 0.99-1.78), and 2.03 (95% CI 1.55-2.65) for total plaque number ≥3, maximum diameter stenosis ≥30%, and plaque score ≥3, respectively. CONCLUSION We demonstrated that prevalences of DM were linearly correlated with prevalences of carotid plaque and DM patients had higher prevalence rates of carotid plaque and more advanced carotid atherosclerosis than non-DM controls. Our results indicated the need to address the role of DM in atherosclerosis development.
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Affiliation(s)
- Tzu-Wei Wu
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
| | - Chao-Liang Chou
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; Department of Neurology, MacKay Memorial Hospital, New Taipei City, Taiwan.
| | - Chun-Fang Cheng
- Tamsui and Bali Health Station, Department of Health, New Taipei City Government, New Taipei City, Taiwan.
| | - Shu-Xin Lu
- Department of Neurology, MacKay Memorial Hospital, New Taipei City, Taiwan.
| | - Li-Yu Wang
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
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Wang T, Xie L, Bi H, Li Y, Li Y, Zhao J. Urantide alleviates the symptoms of atherosclerotic rats in vivo and in vitro models through the JAK2/STAT3 signaling pathway. Eur J Pharmacol 2021; 902:174037. [PMID: 33891969 DOI: 10.1016/j.ejphar.2021.174037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 01/09/2023]
Abstract
Atherosclerosis is the leading cause of human death, and its occurrence and development are related to the urotensin II (UII) and UII receptor (UT) system and the biological function of vascular smooth muscle cells (VSMCs). During atherosclerosis, impaired biological function VSMCs may promote atherosclerotic plaque formation. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is an important mediator of signal transduction; however, the role of this signaling pathway in atherosclerosis and VSMCs remains unknown. This study aimed to investigate the effects of urantide on the JAK2/STAT3 signaling pathway in atherosclerosis. We examined the effect of urantide on the UII/UT system and the JAK2/STAT3 signaling pathway in a high fat diet induced atherosclerosis rat model and studied the effect and mechanism of urantide on the phenotypic transformation of VSMCs. We found that the UII/UT system and JAK2/STAT3 signaling pathway were highly activated in the thoracic aorta in atherosclerotic rats and in ox-LDL- and UII-induced VSMCs. After urantide treatment, the pathological changes in atherosclerotic rats were effectively improved, and the activities of the UII/UT system and JAK2/STAT3 signaling pathway were inhibited. Moreover, urantide effectively inhibited proliferation and migration and reversed the phenotypic transformation of VSMCs. These results demonstrated that urantide may control the JAK2/STAT3 signaling pathway by antagonizing the UII/UT system, thereby maintaining the biological function of VSMCs and potentially preventing and curing atherosclerosis.
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MESH Headings
- Animals
- Aorta/drug effects
- Aorta/pathology
- Atherosclerosis/chemically induced
- Atherosclerosis/drug therapy
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Disease Models, Animal
- Janus Kinase 2/genetics
- Janus Kinase 2/metabolism
- Lipoproteins, LDL/toxicity
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Peptide Fragments/pharmacology
- Peptide Fragments/therapeutic use
- Primary Cell Culture
- Rats, Wistar
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Receptors, G-Protein-Coupled/drug effects
- Receptors, G-Protein-Coupled/metabolism
- STAT3 Transcription Factor/genetics
- STAT3 Transcription Factor/metabolism
- Signal Transduction/drug effects
- Urotensins/antagonists & inhibitors
- Urotensins/metabolism
- Urotensins/pharmacology
- Urotensins/therapeutic use
- Urotensins/toxicity
- Rats
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Affiliation(s)
- Tu Wang
- Department of Pathophysiology, Chengde Medical University, Chengde, Hebei, 067000, China
| | - Lide Xie
- Department of Pathophysiology, Chengde Medical University, Chengde, Hebei, 067000, China
| | - Hongdong Bi
- Department of Pathophysiology, Chengde Medical University, Chengde, Hebei, 067000, China
| | - Ying Li
- Department of Pathophysiology, Chengde Medical University, Chengde, Hebei, 067000, China
| | - Ying Li
- Department of Pathophysiology, Chengde Medical University, Chengde, Hebei, 067000, China
| | - Juan Zhao
- Department of Pathophysiology, Chengde Medical University, Chengde, Hebei, 067000, China.
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Menon S, Vartak R, Patel K, Billack B. Evaluation of the antifungal activity of an ebselen-loaded nanoemulsion in a mouse model of vulvovaginal candidiasis. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 37:102428. [PMID: 34217850 DOI: 10.1016/j.nano.2021.102428] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 04/01/2021] [Accepted: 05/03/2021] [Indexed: 12/20/2022]
Abstract
Vulvovaginal candidiasis (VVC), caused by Candida albicans, is a common infection in women affecting their quality of life. Standard antifungal drugs (e.g., fluconazole, itraconazole) are typically fungistatic or rendered ineffective due to drug resistance indicating an urgent need to build an arsenal of novel antifungal agents. To surmount this issue, we tested the hypothesis that the organoselenium compound ebselen (EB) possesses antifungal efficacy in a mouse model of VVC. EB is a poorly water-soluble drug and DMSO as a vehicle has the potential to exhibit cytotoxic effects when administered in vivo. EB loaded self-nanoemulsifying preconcentrate (EB-SNEP) was developed, characterized in vitro, and tested in a mouse model of VVC. In vivo studies carried out with EB-SNEP (12.5 mg/kg) showed a remarkable decrease in infection by ~562-fold compared to control (infected, untreated animals). Taken together, EB nanoemulsion proved to be an effective and promising antifungal agent.
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Affiliation(s)
- Suvidha Menon
- Department of Pharmaceutical Sciences, St. John's University, Queens, Jamaica, NY, USA
| | - Richa Vartak
- Department of Pharmaceutical Sciences, St. John's University, Queens, Jamaica, NY, USA
| | - Ketankumar Patel
- Department of Pharmaceutical Sciences, St. John's University, Queens, Jamaica, NY, USA.
| | - Blase Billack
- Department of Pharmaceutical Sciences, St. John's University, Queens, Jamaica, NY, USA.
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31
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Choi JSY, de Haan JB, Sharma A. Animal models of diabetes-associated vascular diseases: an update on available models and experimental analysis. Br J Pharmacol 2021; 179:748-769. [PMID: 34131901 DOI: 10.1111/bph.15591] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/08/2021] [Accepted: 06/01/2021] [Indexed: 12/19/2022] Open
Abstract
Diabetes is a chronic metabolic disorder associated with the accelerated development of macrovascular (atherosclerosis and coronary artery disease) and microvascular complications (nephropathy, retinopathy and neuropathy), which remain the principal cause of mortality and morbidity in this population. Current understanding of cellular and molecular pathways of diabetes-driven vascular complications, as well as therapeutic interventions has arisen from studying disease pathogenesis in animal models. Diabetes-associated vascular complications are multi-faceted, involving the interaction between various cellular and molecular pathways. Thus, the choice of an appropriate animal model to study vascular pathogenesis is important in our quest to identify innovative and mechanism-based targeted therapies to reduce the burden of diabetic complications. Herein, we provide up-to-date information on available mouse models of both Type 1 and Type 2 diabetic vascular complications as well as experimental analysis and research outputs.
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Affiliation(s)
- Judy S Y Choi
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Judy B de Haan
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Victoria, Australia.,Faculty of Science, Engineering and Technology, Swinburne University, Melbourne, Victoria, Australia.,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Arpeeta Sharma
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Diabetes, Monash University, Central Clinical School, Melbourne, Victoria, Australia
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Polusani SR, Cortez V, Esparza J, Nguyen HN, Fan H, Velagaleti GVN, Butler MJ, Kinney MC, Oyajobi BO, Habib SL, Asmis R, Medina EA. Oxidatively modified low-density lipoproteins are potential mediators of proteasome inhibitor resistance in multiple myeloma. Int J Cancer 2021; 148:3032-3040. [PMID: 33521927 DOI: 10.1002/ijc.33497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 11/11/2020] [Accepted: 11/30/2020] [Indexed: 11/09/2022]
Abstract
Proteasome inhibitor (PI) therapy has improved the survival of multiple myeloma (MM) patients. However, inevitably, primary or acquired resistance to PIs leads to disease progression; resistance mechanisms are unclear. Obesity is a risk factor for MM mortality. Oxidized LDL (OxLDL), a central mediator of atherosclerosis that is elevated in metabolic syndrome (co-occurrence of obesity, insulin resistance, dyslipidemia and hypertension), has been linked to an increased risk of solid cancers and shown to stimulate pro-oncogenic/survival signaling. We hypothesized that OxLDL is a mediator of chemoresistance and evaluated its effects on MM cell killing by PIs. OxLDL potently suppressed the ability of the boronic acid-based PIs bortezomib (BTZ) and ixazomib, but not the epoxyketone-based PI carfilzomib, to kill human MM cell lines and primary cells. OxLDL suppressed BTZ-induced inhibition of proteasome activity and induction of pro-apoptotic signaling. These cytoprotective effects were abrogated when lipid hydroperoxides (LOOHs) associated with OxLDL were enzymatically reduced. We also demonstrated the presence of OxLDL in the MM bone marrow microenvironment as well as numerous granulocytes and monocytes capable of cell-mediated LDL oxidation through myeloperoxidase. Our findings suggest that OxLDL may be a potent mediator of boronic acid-based PI resistance, particularly for MM patients with metabolic syndrome, given their elevated systemic levels of OxLDL. LDL cholesterol-lowering therapy to reduce circulating OxLDL, and pharmacologic targeting of LOOH levels or resistance pathways induced by the modified lipoprotein, could deepen the response to these important agents and offer clinical benefit to MM patients with metabolic syndrome.
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Affiliation(s)
- Srikanth R Polusani
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Valerie Cortez
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Javier Esparza
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Huynh Nga Nguyen
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Hongxin Fan
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Gopalrao V N Velagaleti
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Matthew J Butler
- Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Marsha C Kinney
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Babatunde O Oyajobi
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, Texas, USA
| | - Samy L Habib
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, Texas, USA.,South Texas Veterans Healthcare System, San Antonio, Texas, USA
| | - Reto Asmis
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Edward A Medina
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Brassington K, Chan SMH, Seow HJ, Dobric A, Bozinovski S, Selemidis S, Vlahos R. Ebselen reduces cigarette smoke-induced endothelial dysfunction in mice. Br J Pharmacol 2021; 178:1805-1818. [PMID: 33523477 PMCID: PMC8074626 DOI: 10.1111/bph.15400] [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: 09/03/2020] [Revised: 12/21/2020] [Accepted: 01/20/2021] [Indexed: 12/26/2022] Open
Abstract
Background and Purpose It is well established that both smokers and patients with COPD are at a significantly heightened risk of cardiovascular disease (CVD), although the mechanisms underpinning the onset and progression of co‐morbid CVD are largely unknown. Here, we explored whether cigarette smoke (CS) exposure impairs vascular function in mice and given the well‐known pathological role for oxidative stress in COPD, whether the antioxidant compound ebselen prevents CS‐induced vascular dysfunction in mice. Experimental Approach Male BALB/c mice were exposed to either room air (sham) or CS generated from nine cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10 mg·kg−1, oral gavage once daily) or vehicle (5% w/v CM cellulose in water) 1 h prior to the first CS exposure of the day. Upon killing, bronchoalveolar lavage fluid (BALF) was collected to assess pulmonary inflammation, and the thoracic aorta was excised to investigate vascular endothelial and smooth muscle dilator responses ex vivo. Key Results CS exposure caused a significant increase in lung inflammation which was reduced by ebselen. CS also caused significant endothelial dysfunction in the thoracic aorta which was attributed to a down‐regulation of eNOS expression and increased vascular oxidative stress. Ebselen abolished the aortic endothelial dysfunction seen in CS‐exposed mice by reducing the oxidative burden and preserving eNOS expression. Conclusion and Implications Targeting CS‐induced oxidative stress with ebselen may provide a novel means for treating the life‐threatening pulmonary and cardiovascular manifestations associated with cigarette smoking and COPD.
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Affiliation(s)
- Kurt Brassington
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Stanley M H Chan
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Huei Jiunn Seow
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Aleksandar Dobric
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Steven Bozinovski
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Stavros Selemidis
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Ross Vlahos
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
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Al Aboud D, Baty RS, Alsharif KF, Hassan KE, Zhery AS, Habotta OA, Elmahallawy EK, Amin HK, Abdel Moneim AE, Kassab RB. Protective efficacy of thymoquinone or ebselen separately against arsenic-induced hepatotoxicity in rat. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:6195-6206. [PMID: 32989703 DOI: 10.1007/s11356-020-10955-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/20/2020] [Indexed: 05/12/2023]
Abstract
Arsenic (As) exposure is associated with adverse health outcomes to the living organisms. In the present study, the hepato-protective ability of thymoquinone (TQ), the active principle of Nigella sativa seed, or ebselen (Eb), an organoselenium compound, against As intoxication in female rats was investigated. For this purpose, animals were allocated randomly into control, As (20 mg/kg), TQ (10 mg/kg), Eb (5 mg/kg), As+TQ, and As+Eb groups that were orally administered for 28 consecutive days. Arsenic exposure resulted in hepatic oxidative damage which was evidenced by marked decreases in antioxidant parameters (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH)) concomitant with high malondialdehyde (MDA) level. Furthermore, As toxicity induced significant elevations in liver accumulation of As, serum hepatic indices (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin (TB)), and apoptotic marker (B cell lymphoma 2(Bcl2), Bcl-2-associated X protein (Bax), and caspase 3) levels. Additionally, notable increments in hepatic fibrotic markers (epidermal growth factor (EFG) and transforming growth factor beta 1 (TGF-β1)) associated with high nitric oxide, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and myeloperoxidase (MPO) levels were noticed following As intoxication. Biochemical findings were well-supported by hepatic histopathological screening. The co-treatment of As-exposed rats with TQ or Eb considerably improved liver function and antioxidant status together with lessened hepatic As content, inflammation, apoptosis, and fibrosis. The overall outcomes demonstrated that TQ or Eb ameliorates As-induced liver injury through their favorable antioxidant, anti-inflammatory, anti-apoptotic, and fibrolytic properties.
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Affiliation(s)
- Daifullah Al Aboud
- Department of Internal Medicine, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Roua S Baty
- Biotechnology Department, College of Science, Taif University, Taif, Saudi Arabia
| | - Khalaf F Alsharif
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, Taif University, Taif, P.O. Box 11099, Taif 21944, Saudi Arabia
| | | | - Ahmed S Zhery
- Kasr Al-Eini School of Medicine, Cairo University, Cairo, Egypt
| | - Ola A Habotta
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Ehab K Elmahallawy
- Department of Zoonotic Diseases, Faculty of Veterinary Medicine, Sohag University, Sohag, 82524, Egypt.
| | - Hatim K Amin
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Ahmed E Abdel Moneim
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, 11795, Egypt
| | - Rami B Kassab
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, 11795, Egypt
- Department of Biology, Faculty of Science and Arts, Al Baha University, Almakhwah, Al Baha, Saudi Arabia
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Hong YA, Park CW. Catalytic Antioxidants in the Kidney. Antioxidants (Basel) 2021; 10:antiox10010130. [PMID: 33477607 PMCID: PMC7831323 DOI: 10.3390/antiox10010130] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 02/08/2023] Open
Abstract
Reactive oxygen species and reactive nitrogen species are highly implicated in kidney injuries that include acute kidney injury, chronic kidney disease, hypertensive nephropathy, and diabetic nephropathy. Therefore, antioxidant agents are promising therapeutic strategies for kidney diseases. Catalytic antioxidants are defined as small molecular mimics of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, and some of them function as potent detoxifiers of lipid peroxides and peroxynitrite. Several catalytic antioxidants have been demonstrated to be effective in a variety of in vitro and in vivo disease models that are associated with oxidative stress, including kidney diseases. This review summarizes the evidence for the role of antioxidant enzymes in kidney diseases, the classifications of catalytic antioxidants, and their current applications to kidney diseases.
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Affiliation(s)
- Yu Ah Hong
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Cheol Whee Park
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
- Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- Correspondence: ; Tel.: +82-2-2258-6038
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Charlton A, Garzarella J, Jandeleit-Dahm KAM, Jha JC. Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes. BIOLOGY 2020; 10:biology10010018. [PMID: 33396868 PMCID: PMC7830433 DOI: 10.3390/biology10010018] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/17/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023]
Abstract
Simple Summary The progressive nature of type 2 diabetes mellitus (T2DM) leads to micro- and macro-vascular complications, including renal and cardiovascular disease. These alone, or in combination, are a major cause of premature morbidity and mortality in diabetic patients. Despite advances in glucose lowering treatments, these diabetic complications are still inadequately prevented or reversed. This ongoing cardiovascular–renal burden in diabetes poses a heavy cost on the health care system. Therefore, there is an urgent need to develop more effective treatments. In this review, we discuss how oxidative stress and inflammation induce and perpetuate the renal and cardiovascular complications of diabetes. It is particularly important to understand these driving mechanisms in order to elucidate pharmacological targets and mechanism-based future drug therapies. Abstract Oxidative stress and inflammation are considered major drivers in the pathogenesis of diabetic complications, including renal and cardiovascular disease. A symbiotic relationship also appears to exist between oxidative stress and inflammation. Several emerging therapies target these crucial pathways, to alleviate the burden of the aforementioned diseases. Oxidative stress refers to an imbalance between reactive oxygen species (ROS) and antioxidant defenses, a pathological state which not only leads to direct cellular damage but also an inflammatory cascade that further perpetuates tissue injury. Emerging therapeutic strategies tackle these pathways in a variety of ways, from increasing antioxidant defenses (antioxidants and Nrf2 activators) to reducing ROS production (NADPH oxidase inhibitors and XO inhibitors) or inhibiting the associated inflammatory pathways (NLRP3 inflammasome inhibitors, lipoxins, GLP-1 receptor agonists, and AT-1 receptor antagonists). This review summarizes the mechanisms by which oxidative stress and inflammation contribute to and perpetuate diabetes associated renal and cardiovascular disease along with the therapeutic strategies which target these pathways to provide reno and cardiovascular protection in the setting of diabetes.
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Affiliation(s)
- Amelia Charlton
- Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia; (A.C.); (J.G.); (K.A.M.J.-D.)
| | - Jessica Garzarella
- Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia; (A.C.); (J.G.); (K.A.M.J.-D.)
| | - Karin A. M. Jandeleit-Dahm
- Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia; (A.C.); (J.G.); (K.A.M.J.-D.)
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University, Dusseldorf 40225, Germany
| | - Jay C. Jha
- Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia; (A.C.); (J.G.); (K.A.M.J.-D.)
- Correspondence:
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Jung HY, Oh SH, Ahn JS, Oh EJ, Kim YJ, Kim CD, Park SH, Kim YL, Cho JH. NOX1 Inhibition Attenuates Kidney Ischemia-Reperfusion Injury via Inhibition of ROS-Mediated ERK Signaling. Int J Mol Sci 2020; 21:ijms21186911. [PMID: 32967113 PMCID: PMC7554761 DOI: 10.3390/ijms21186911] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/13/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin–Darby Canine Kidney (MDCK) cells were incubated with H2O2 (1.4 mM) for 1 h to induce oxidative stress. ML171, a selective NOX1 inhibitor, and siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of reactive oxygen species (ROS), including intracellular H2O2 production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by ML171. H2O2 evoked the changes in oxidative stress enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by ML171. Treatment with ML171 and transfection with siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H2O2 in MDCK cells. ML171 decreased caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H2O2-treated MDCK cells. Among the MAPK pathways, ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jang-Hee Cho
- Correspondence: ; Tel.: +82-10-6566-7551; Fax: +82-53-426-2046
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Urner S, Ho F, Jha JC, Ziegler D, Jandeleit-Dahm K. NADPH Oxidase Inhibition: Preclinical and Clinical Studies in Diabetic Complications. Antioxid Redox Signal 2020; 33:415-434. [PMID: 32008354 DOI: 10.1089/ars.2020.8047] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Significance: Oxidative stress plays a critical role in the development and progression of serious micro- and macrovascular complications of diabetes. Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) significantly contribute to oxidative stress-associated inflammatory pathways that lead to tissue damage of different organs, including the kidneys, retina, brain, nerves, and the cardiovascular system. Recent Advances: Preclinical studies, including genetic-modified mouse models or cell culture models, have revealed the role of specific NOX isoforms in different diabetic complications, and suggested them as a promising target for the treatment of these diseases. Critical Issues: In this review, we provide an overview of the role of ROS and oxidative stress in macrovascular complications, such as stroke, myocardial infarction, coronary artery disease, and peripheral vascular disease that are all mainly driven by atherosclerosis, as well as microvascular complications, such as diabetic retinopathy, nephropathy, and neuropathy. We summarize conducted genetic deletion studies of different Nox isoforms as well as pharmacological intervention studies using NOX inhibitors in the context of preclinical as well as clinical research on diabetic complications. Future Directions: We outline the isoforms that are most promising for future clinical trials in the context of micro- and macrovascular complications of diabetes.
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Affiliation(s)
- Sofia Urner
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany
| | - Florence Ho
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Jay C Jha
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany
| | - Karin Jandeleit-Dahm
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
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Kose A, Kose D, Halici Z, Aydin A, Ezirmik N, Karsan O, Toktay E. Is Ebselen A Therapeutic Target in Fracture Healing? Eurasian J Med 2020; 52:171-175. [PMID: 32612426 DOI: 10.5152/eurasianjmed.2020.18443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 04/16/2019] [Indexed: 11/22/2022] Open
Abstract
Objective We investigated the effect of ebselen on fracture healing in an experimental fracture model. Materials and Methods We divided rats into two groups, 6 rats in each: the experimental femur fracture control group and the ebselen treatment group with an experimental femur fracture. In the experimental femur fracture control group, we created only experimental femur fracture. In the ebselen treatment group, we administered ebselen treatment with creating an experimental femur fracture. We administered ebselen intraperitoneally at 5 mg/kg once daily for 1 month after the 1st day of experimental femur fracture in the ebselen treatment group. We evaluated the recovery status of fractured femurs at the end of 1st month with radiographic, histopathological, and immunohistochemical methods. Results According to the radiographic fracture healing scores, ebselen treatment increased the extent of new bone formation and fracture cartilage callus significantly compared to the control group. According to the histopathological recovery scores, ebselen treatment significantly improved healing scores compared to the control group. Ebselen treatment increased the expression scores of bone healing markers in the ebselen treatment group, such as vascular endothelial growth factor and osteocalcin, compared to the control group. Conclusion We demonstrated that ebselen treatment increases the formation of new bone in the femur in an experimentally created femoral fracture model. Ebselen has been shown to improve the bone fracture healing in a radiological and histopathological manner, and more detailed studies are needed.
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Affiliation(s)
- Ahmet Kose
- Department of Orthophedics and Traumatology, Erzurum Regional Training and Research Hospital, Erzurum, Turkey
| | - Duygu Kose
- Department of Pharmacology, Ataturk University School of Medicine, Erzurum, Turkey
| | - Zekai Halici
- Department of Pharmacology, Ataturk University School of Medicine, Erzurum, Turkey
| | - Ali Aydin
- Department of Orthophedics and Traumatology, Ataturk University School of Medicine, Erzurum, Turkey
| | - Naci Ezirmik
- Department of Orthophedics and Traumatology, Ataturk University School of Medicine, Erzurum, Turkey
| | - Orhan Karsan
- Department of Orthophedics and Traumatology, Ataturk University School of Medicine, Erzurum, Turkey
| | - Erdem Toktay
- Department of Histology and Embryology, Ataturk University, School of Medicine, Erzurum, Turkey
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40
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Targeting oxidative stress and anti-oxidant defence in diabetic kidney disease. J Nephrol 2020; 33:917-929. [DOI: 10.1007/s40620-020-00749-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
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41
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Urotensin receptor antagonist urantide improves atherosclerosis-related kidney injury by inhibiting JAK2/STAT3 signaling pathway in rats. Life Sci 2020; 247:117421. [DOI: 10.1016/j.lfs.2020.117421] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/05/2020] [Accepted: 02/08/2020] [Indexed: 12/16/2022]
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The Diabetes Mellitus-Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation. Int J Mol Sci 2020; 21:ijms21051835. [PMID: 32155866 PMCID: PMC7084712 DOI: 10.3390/ijms21051835] [Citation(s) in RCA: 611] [Impact Index Per Article: 122.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities in proteins, lipids, and carbohydrates. Atherosclerosis develops as a result of a multistep process ultimately leading to cardiovascular disease associated with high morbidity and mortality. Alteration of lipid metabolism is a risk factor and characteristic feature of atherosclerosis. Possible links between the two chronic disorders depending on altered metabolic pathways have been investigated in numerous studies. It was shown that both types of diabetes mellitus can actually induce atherosclerosis development or further accelerate its progression. Elevated glucose level, dyslipidemia, and other metabolic alterations that accompany the disease development are tightly involved in the pathogenesis of atherosclerosis at almost every step of the atherogenic process. Chronic inflammation is currently considered as one of the key factors in atherosclerosis development and is present starting from the earliest stages of the pathology initiation. It may also be regarded as one of the possible links between atherosclerosis and diabetes mellitus. However, the data available so far do not allow for developing effective anti-inflammatory therapeutic strategies that would stop atherosclerotic lesion progression or induce lesion reduction. In this review, we summarize the main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship with chronic inflammation. We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications.
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Negre-Salvayre A, Guerby P, Gayral S, Laffargue M, Salvayre R. Role of reactive oxygen species in atherosclerosis: Lessons from murine genetic models. Free Radic Biol Med 2020; 149:8-22. [PMID: 31669759 DOI: 10.1016/j.freeradbiomed.2019.10.011] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/16/2019] [Accepted: 10/16/2019] [Indexed: 12/19/2022]
Abstract
Atherosclerosis is a multifactorial chronic and inflammatory disease of medium and large arteries, and the major cause of cardiovascular morbidity and mortality worldwide. The pathogenesis of atherosclerosis involves a number of risk factors and complex events including hypercholesterolemia, endothelial dysfunction, increased permeability to low density lipoproteins (LDL) and their sequestration on extracellular matrix in the intima of lesion-prone areas. These events promote LDL modifications, particularly by oxidation, which generates acute and chronic inflammatory responses implicated in atherogenesis and lesion progression. Reactive oxygen species (ROS) (which include both free radical and non-free radical oxygen intermediates), play a key-role at each step of atherogenesis, in endothelial dysfunction, LDL oxidation, and inflammatory events involved in the initiation and development of atherosclerosis lesions. Most advanced knowledge supporting the "oxidative theory of atherosclerosis" i.e. the nature and the cellular sources of ROS and antioxidant defences, as well as the mechanisms involved in the redox balance, is based on the use of genetically engineered animals, i.e. transgenic, genetically modified, or altered for systems producing or neutralizing ROS in the vessels. This review summarizes the results obtained from animals genetically manipulated for various sources of ROS or antioxidant defences in the vascular wall, and their relevance (advance or limitation), for understanding the place and role of ROS in atherosclerosis.
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Affiliation(s)
| | - Paul Guerby
- Inserm U-1048, Université de Toulouse, France; Pôle de gynécologie obstétrique, Hôpital Paule-de-Viguier, CHU de Toulouse, France
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Dong W, Chen H, Wang L, Cao X, Bu X, Peng Y, Dong A, Ying M, Chen X, Zhang X, Yao L. Exploring the shared genes of hypertension, diabetes and hyperlipidemia based on microarray. BRAZ J PHARM SCI 2020. [DOI: 10.1590/s2175-97902020000118333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Wenzhu Dong
- Zhejiang Chinese Medical University, P.R. China; Taizhou Central Hospital, P.R. China
| | | | - Lu Wang
- Zhejiang Chinese Medical University, P.R. China
| | | | - Xiawei Bu
- Zhejiang Chinese Medical University, P.R. China
| | - Yan Peng
- Zhejiang Chinese Medical University, P.R. China
| | | | | | - Xu Chen
- Taizhou Central Hospital, P.R. China
| | - Xin Zhang
- Taizhou Central Hospital, P.R. China
| | - Li Yao
- Zhejiang Chinese Medical University, P.R. China
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Ozer MK, Bilgic S, Armagan I, Savran M. Thymoquinone protection from amikacin induced renal injury in rats. Biotech Histochem 2019; 95:129-136. [PMID: 31502890 DOI: 10.1080/10520295.2019.1650957] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We investigated whether thymoquinone (TQ) exerts a beneficial effect on renal injury due to amikacin (AK) administration in rats. To generate kidney damage with AK, a single 1.2 g/kg dose of AK was administered intraperitoneally. TQ was administered orally to the AK treated group at a dose of 40 mg/kg for five days. At the end of the experiment, rats were sacrificed and blood samples were used to measure blood urea nitrogen (BUN) and creatinine (Cr) levels. Kidney samples were taken to measure the oxidative stress biomarker, malondialdehyde (MDA), and expression of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT). Because reactive oxygen species (ROS) and apoptosis contribute to tissue damage associated with NADPH oxidase (NOX), we also investigated NOX-2, NOX-4 and apoptosis marker, caspase-3, expression using immunohistochemistry. MDA, BUN, Cr, NOX-2, NOX-4 and caspase-3 production were increased, and SOD and CAT were decreased in the AK treated group compared to controls. MDA, BUN, Cr, NOX-2, NOX-4 and caspase-3 levels were decreased, and SOD and CAT levels were increased in TQ + AK treated rats compared to AK treated animals. TQ appears to protect the kidney from the toxic effects of AK.
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Affiliation(s)
- M K Ozer
- Department of Pharmacology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
| | - S Bilgic
- Department of Biochemistry, Vocational School of Health Services, Adiyaman University, Adiyaman, Turkey
| | - I Armagan
- Department of Histology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - M Savran
- Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
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Li Y, Chen G, He Y, Zhang X, Zeng B, Wang C, Yi C, Yu D. Ebselen rescues oxidative-stress-suppressed osteogenic differentiation of bone-marrow-derived mesenchymal stem cells via an antioxidant effect and the PI3K/Akt pathway. J Trace Elem Med Biol 2019; 55:64-70. [PMID: 31345368 DOI: 10.1016/j.jtemb.2019.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Patients with metabolic bone diseases often have high risk of titanium implant failure due to compromised bone regeneration ability. Clinical evidence indicates that the poor osteogenic ability is partly because of excessive oxidative stress. To date, specific treatments for these patients are urgently needed. Ebselen, a non-toxic organoselenium compound, is reported to be a potent antioxidant agent. In this study, we hypothesized that ebselen exerted protective effects on osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress. METHODS BMSCs were isolated from SD rats, and their morphology and multiple differentiation abilities were characterized. Proliferation rates of BMSCs treated with different concentrations of ebselen were analyzed. Then BMSCs were pretreated by hydrogen peroxide (H2O2), after which ebselen at different concentrations (0, 1, 5, 10 μM) was added, alkaline phosphatase (ALP) activity, mineralization and osteogenic-related protein levels were evaluated and an optimum concentration of ebselen was selected. Subsequently, intracellular reactive oxygen species (ROS) generation and the role of the PI3K/AKT pathway were also investigated. RESULTS Ebselen within a proper range could promote the proliferation of BMSCs. H2O2-induced oxidative stress suppressed osteogenic differentiation of BMSCs, which was verified by the decrease in ALP activity, calcium deposition, Runx2 and β-catenin expression. However, ebselen could alleviate osteogenic dysfunction of BMSCs. We also observed that ebselen reduced ROS accumulation in H2O2-pretreated BMSCs. Moreover, the pro-osteogenic effects afforded by ebselen were almost abolished by the Akt inhibitor. CONCLUSION We concluded that ebselen could attenuate osteogenic dysfunction of BMSCs induced by H2O2 through an antioxidant effect and the activation of the PI3K/Akt pathway, suggesting that ebselen has a potential therapeutic effect for patients with metabolic bone diseases.
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Affiliation(s)
- Yiming Li
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Guanhui Chen
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Yi He
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Xiliu Zhang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Binghui Zeng
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Chao Wang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Chen Yi
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China
| | - Dongsheng Yu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, PR China.
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Réus GZ, Carlessi AS, Silva RH, Ceretta LB, Quevedo J. Relationship of Oxidative Stress as a Link between Diabetes Mellitus and Major Depressive Disorder. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8637970. [PMID: 30944699 PMCID: PMC6421821 DOI: 10.1155/2019/8637970] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 01/21/2019] [Accepted: 02/14/2019] [Indexed: 02/06/2023]
Abstract
Both conditions, major depressive disorder (MDD) and diabetes mellitus (DM) are chronic and disabling diseases that affect a very significant percentage of the world's population. Studies have been shown that patients with DM are more susceptible to develop depression, when compared to the general population. The opposite also happens; MDD could be a risk factor for DM development. Some mechanisms have been proposed to explain the pathophysiological mechanisms involved with these conditions, such as excess of glucocorticoids, hyperglycemia, insulin resistance, and inflammation. These processes can lead to an increase in damage to biomolecules and a decrease in antioxidant defense capacity, leading to oxidative stress.
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Affiliation(s)
- Gislaine Z. Réus
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Anelise S. Carlessi
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Ritele H. Silva
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Luciane B. Ceretta
- Programa de Pós-graduação em Saúde Coletiva, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - João Quevedo
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil
- Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Neuroscience Graduate Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
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Bucak MN, Bodu M, Başpınar N, Güngör Ş, İli P, Acibaeva B, Topraggaleh TR, Dursun Ş. Influence of Ellagic Acid and Ebselen on Sperm and Oxidative Stress Parameters during Liquid Preservation of Ram Semen. CELL JOURNAL 2018; 21:7-13. [PMID: 30507083 PMCID: PMC6275427 DOI: 10.22074/cellj.2019.5593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 04/10/2018] [Indexed: 11/04/2022]
Abstract
Objective The purpose of the present study was to assess the effects of ellagic acid and ebselen on sperm and oxidative stress parameters during liquid preservation of ram semen. Materials and Methods In this experimental study, sixty ejaculates from six mature Merino rams were used. In experiment 1, the ejaculates were diluted in base extender contained ellagic acid at 0 (control), 0.5, 1, and 2 mM. In experiment 2, ebselen at 0 (control), 10, 20, and 40 μM were added to the extender. Sperm motility, viability, mitochondrial membrane potential, DNA integrity, lipid peroxidation (LPO), the antioxidant potential (AOP), and total glutathione (tGSH) were evaluated at 0, 24, 48, and 72 hours of preservation. Results Supplementation of ellagic acid at 1 and 2 mM resulted in higher sperm motility and viability at 0 hours of storage. Ellagic acid at 2 mM led to higher motility and viability compared to controls after 0, 24, and 48 hours of preservation and increased AOP after 24 and 72 hours. Higher tGSH was at 1 mM ellagic acid, compared to control after 72 hours. Addition of ebselen at a concentration of 40 μM increased motility at 24 and 48 hours and 10 μM produced the same effect after 48 and 72 hours of storage as well as higher viability, compared to the controls after 0 hours of storage. Sperm DNA integrity was significantly improved after 24, 48, and 72 hours with the addition of ebselen at 10 μM, and after 72 hours at 40 μM. Addition of 40 mM ebselen also reduced the LPO levels after 24 hours of storage compared to the controls. Conclusion The results showed that supplementation of ellagic acid and ebselen in semen extender has a potential effect on sperm and oxidative stress parameters during liquid preservation of ram semen.
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Affiliation(s)
- Mustafa Numan Bucak
- Department of Reproduction and Artificial Insemination, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey. Electronic Address:
| | - Mustafa Bodu
- Department of Reproduction and Artificial Insemination, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey
| | - Nuri Başpınar
- Department of Biochemistry, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey
| | - Şükrü Güngör
- Department of Reproduction and Artificial Insemination, Faculty of Veterinary Medicine, Mehmet Akif Ersoy University, Burdur, Turkey
| | - Pınar İli
- Pamukkale University, Denizli Health Services Vocational High School, Denizli, Turkey
| | - Begimay Acibaeva
- Pamukkale University, Denizli Health Services Vocational High School, Denizli, Turkey
| | - Tohid Rezaei Topraggaleh
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Inistitute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Şükrü Dursun
- Department of Gynecology and Obstetrics, Faculty of Veterinary Medicine, Aksaray University, Aksaray, Turkey
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Huang JQ, Zhou JC, Wu YY, Ren FZ, Lei XG. Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases. Free Radic Biol Med 2018; 127:108-115. [PMID: 29800654 PMCID: PMC6168395 DOI: 10.1016/j.freeradbiomed.2018.05.077] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 05/20/2018] [Accepted: 05/21/2018] [Indexed: 01/14/2023]
Abstract
Glutathione peroxidase 1 (GPX1) is a selenium-dependent enzyme that reduces intracellular hydrogen peroxide and lipid peroxides. While past research explored regulations of gene expression and biochemical function of this selenoperoxidase, GPX1 has recently been implicated in the onset and development of chronic diseases. Clinical data have shown associations of human GPX1 gene variants with elevated risks of diabetes. Knockout and overexpression of Gpx1 in mice may induce types 1 and 2 diabetes-like phenotypes, respectively. This review assembles the latest advances in this new field of selenium biology, and attempts to postulate signal and molecular mechanisms mediating the role of GPX1 in glucose and lipid metabolism-related diseases. Potential therapies by harnessing the beneficial effects of this ubiquitous redox-modulating enzyme are briefly discussed.
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Affiliation(s)
- Jia-Qiang Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China; Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, China
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen 518100, China; Molecular Biology Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen 518020, China
| | - Yuan-Yuan Wu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China
| | - Fa-Zheng Ren
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China; Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, China
| | - Xin Gen Lei
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China; Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
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Negi CK, Jena G. Nrf2, a novel molecular target to reduce type 1 diabetes associated secondary complications: The basic considerations. Eur J Pharmacol 2018; 843:12-26. [PMID: 30359563 DOI: 10.1016/j.ejphar.2018.10.026] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 10/10/2018] [Accepted: 10/17/2018] [Indexed: 12/30/2022]
Abstract
Oxidative stress and inflammation are the mediators of diabetes and related secondary complications. Oxidative stress arises because of the excessive production of reactive oxygen species and diminished antioxidant production due to impaired Nrf2 activation, the master regulator of endogenous antioxidant. It has been established from various animal models that the transcription factor Nrf2 provides cytoprotection, ameliorates oxidative stress, inflammation and delays the progression of diabetes and its associated complications. Whereas, deletion of the transcription factor Nrf2 amplifies tissue level pathogenic alterations. In addition, Nrf2 also regulates the expression of numerous cellular defensive genes and protects against oxidative stress-mediated injuries in diabetes. The present review provides an overview on the role of Nrf2 in type 1 diabetes and explores if it could be a potential target for the treatment of diabetes and related complications. Further, the rationality of different agent's intervention has been discussed to mitigate organ damages induced by diabetes.
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Affiliation(s)
- Chander K Negi
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India.
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