Dapagliflozin in Chronic Kidney Disease: Insights from Network Pharmacology and Molecular Docking Simulation

Life, Journal Year: 2025, Volume and Issue: 15(3), P. 437 - 437

Published: March 11, 2025

Chronic kidney disease (CKD) involves inflammation, oxidative stress, and fibrosis, leading to renal dysfunction. Dapagliflozin, an SGLT2 inhibitor, shows renoprotective effects beyond glucose control, but its precise molecular mechanisms remain unclear. This study utilizes network pharmacology docking elucidate multi-target in CKD. Dapagliflozin’s SMILES structure was analyzed for ADMET properties. Potential targets were identified via SwissTargetPrediction, GeneCards, SEA, common CKD-related determined. A protein–protein interaction (PPI) constructed, key pathways using GO KEGG enrichment analyses. Molecular conducted validate dapagliflozin’s binding affinities with hub proteins. total of 208 identified, including EGFR, GSK3β, IL-6. analyses highlighted pathways, such as PI3K-Akt, MAPK, AGE-RAGE, involved metabolic regulation. confirmed strong EGFR (−8.42 kcal/mol), GSK3β (−7.70 IL-6 (−6.83 kcal/mol). Dapagliflozin exhibits therapeutic potential CKD by modulating pathways. integrative approach enhances the understanding mechanisms, supporting future experimental validation clinical application management.

Language: Английский

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RAGE Inhibitors in Neurodegenerative Diseases

Biomedicines, Journal Year: 2023, Volume and Issue: 11(4), P. 1131 - 1131

Published: April 9, 2023

Nonenzymatic reactions of reducing sugars with primary amino groups acids, proteins, and nucleic followed by oxidative degradations would lead to the formation advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading onset neurological disorders. interaction receptors for (RAGE) contribute activation intracellular signaling expression pro-inflammatory transcription factors various inflammatory cytokines. This cascade is associated diseases, including Alzheimer’s disease (AD), secondary traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, other AGE-related diabetes atherosclerosis. Furthermore, imbalance gut microbiota intestinal inflammation are also endothelial dysfunction, disrupted blood–brain barrier (BBB) thereby progression AD diseases. RAGE play an important role in altering composition increase permeability affect modulation immune-related inhibition AGE–RAGE interactions, through small molecule-based therapeutics, prevents events attenuates progression. Some antagonists, such as Azeliragon, currently clinical development treating AD, although there have been no FDA-approved therapeutics based antagonists. review outlines interactions a cause diseases current efforts developing

Language: Английский

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Mechanisms of long COVID: An updated review

Chinese Medical Journal - Pulmonary and Critical Care Medicine, Journal Year: 2023, Volume and Issue: 1(4), P. 231 - 240

Published: Dec. 1, 2023

The coronavirus disease 2019 (COVID-19) pandemic has been ongoing for more than 3 years, with an enormous impact on global health and economies. In some patients, symptoms signs may remain after recovery from severe acute respiratory syndrome 2 (SARS-CoV-2) infection, which cannot be explained by alternate diagnosis; this condition defined as long COVID. Long COVID exist in patients both mild is prevalent infection different SARS-CoV-2 variants. most common include fatigue, dyspnea, other involving multiple organs. Vaccination results lower rates of To date, the mechanisms unclear. narrative review, we summarized clinical presentations current evidence regarding pathogenesis

Language: Английский

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Pharmacological targets of SGLT2 inhibitors on IgA nephropathy and membranous nephropathy: a mendelian randomization study

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 22, 2024

Introduction Emerging research suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may play a pivotal role in the treatment of primary glomerular diseases. This study was aimed to investigate potential pharmacological targets connecting SGLT2 with IgA nephropathy (IgAN) and membranous (MN). Methods A univariate Mendelian randomization (MR) analysis conducted using publicly available genome-wide association studies (GWAS) datasets. Co-localization used identify connections between target genes IgAN MN. Then, Comparative Toxicogenomics Database (CTD) employed predict diseases associated these (canagliflozin, dapagliflozin, empagliflozin). Subsequently, phenotypic scan analyses were applied explore causal relationships predicted genes. Finally, we analyzed immune signaling pathways involving Kyoto encyclopedia genomes (KEGG). Results The results MR revealed eight drug causally linked occurrence IgAN, while 14 In case LCN2 AGER emerged as co-localized related agent dapagliflozin IgAN. identified risk factor, exhibited protective role. KEGG is involved interleukin (IL)-17 pathway, neutrophil extracellular traps (NETs) pathway. No positive co-localization observed two other (canagliflozin empagliflozin) nor three Conclusion Our provided evidence supporting relationship specific Furthermore, found act on through AGER.

Language: Английский

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Antiviral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models

The Journal of Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 5, 2024

Abstract SARS-CoV-2 variants of concern (VOCs) continue to evolve and reemerge with chronic inflammatory long COVID sequelae, necessitating the development anti-inflammatory therapeutic molecules. Therapeutic effects receptor for advanced glycation end products (RAGE) were reported in many diseases. However, a effect RAGE COVID-19 has not been reported. In present study, we investigated whether how RAGE-Ig fusion protein would have an antiviral system. The protective was determined vivo K18-hACE2 transgenic mice Syrian golden hamsters infected six VOCs SARS-CoV-2. underlying mechanism vitro SARS-CoV-2–infected human lung epithelial cells (BEAS-2B). Following treatment various RAGE-Ig, demonstrated (1) significant dose-dependent protection (i.e., greater survival, less weight loss, lower virus replication lungs); (2) reduction macrophages (F4/80+/Ly6C+) neutrophils (CD11b+/Ly6G+) infiltrating lungs; (3) increase expression type I IFNs (IFN-α IFN-β) III IFN (IFNλ2) decrease cytokines (IL-6 IL-8) cells; (4) CD64 (FcgR1) on monocytes from symptomatic patients. Our preclinical findings revealed IFN-mediated against caused by multiple VOCs.

Language: Английский

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Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 22, 2024

Abstract Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, aim of this study was to assess selected nitrosative parameters glycoxidation products in COVID-19 patients convalescents relative healthy subjects, including reference severity symptoms. The diagnostic utility biomarkers also evaluated patients. involved 218 COVID-19, 69 convalescents, 48 subjects. (NO, S-nitrosothiols, nitrotyrosine) (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured blood plasma or serum use colorimetric/fluorometric methods. levels NO ( p = 0.0480), S-nitrosothiols 0.0004), nitrotyrosine 0.0175), kynurenine < 0.0001), N-formylkynurenine dityrosine AGEs 0.0001) significantly higher, whereas tryptophan fluorescence lower than control group. Significant differences analyzed observed different stages COVID-19. In turn, concentrations controls. ROC analysis revealed that be useful for diagnosing infections virus because they differentiate (KN: sensitivity—91.20%, specificity—92.00%; NFK: sensitivity—92.37%, AGEs: sensitivity—99,02%, specificity—100%) sensitivity—82.22%, specificity—84.00%; sensitivity—82,86%, specificity—86,00%; DT: sensitivity—100%, specificity—100%; AGE: from subjects high sensitivity specificity. are intensified after redox fluctuate disease. Circulating stress/protein have potential convalescents.

Language: Английский

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Calycosin and kidney health: a molecular perspective on its protective mechanisms

Pharmacological Reports, Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Language: Английский

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Hematological Markers in Thromboembolic Events: A Comparative Study of COVID-19 and Non-COVID-19 Hospitalized Patients

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(9), P. 3192 - 3192

Published: May 5, 2025

Background/Objectives: SARS-CoV-2 infection increases thrombotic events in hospitalized patients, especially those of greater severity. It has been associated with the cytokine storm and worsening renal liver function, increased inflammatory markers, altered coagulation markers. This study analyzes differences inflammatory, hepatic, renal, markers between patients without COVID-19 who experienced thromboembolic during last three years pandemic. Methods: single-center, retrospective observational study, an inferential component biomarker analysis, included 663 (600 COVID-19, 63 COVID-19) admitted December 2022 January 2023. Results: Patients exhibited significantly higher mean glomerular filtration rate (GFR) (100.5 mL/min/1.73 m2; p < 0.01) alanine aminotransferase (ALT) levels (33.0 IU/L; compared to COVID-19. Ferritin were also elevated (441.1; 0.01), particularly severe disease. Conversely, troponin I was (22.6 × 104 pg/mL; 0.001). Among D-dimer not requiring intensive care unit (ICU) admission (9.0 103 ng/mL; = 0.023). Multivariate analysis revealed a significant association sex. Conclusions: Overall, function did differ non-COVID-19 patients. However, better ICU, regardless status. Troponin while ferritin ALT showed no difference two groups.

Language: Английский

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Spinach Extract Reduces Kidney Damage in Diabetic Rats by Impairing the AGEs/RAGE Axis

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(10), P. 4730 - 4730

Published: May 15, 2025

The interaction between advanced glycation end products (AGEs) and their RAGE receptor (AGEs/RAGE axis) triggers several signaling pathways that lead to the development of diabetic nephropathy (DN). One most studied AGEs is Nε-(1-Carboxymethyl)-L-lysine (CML). Spinacia oleracea an edible plant with beneficial health properties, but its effect on AGE/RAGE axis in kidney damage unknown. Objective: We aimed investigate functional role spinach methanolic extract (SME) rats associated CML/RAGE axis. Methods: Forty adult male Wistar were used this study divided into four groups: control (CTRL), SME-administered CTRL (400 mg/kg; SME), streptozotocin-induced (STZ), SME-treated STZ (STZ-SME); treatments administered daily. After 12 weeks, serum AGEs, creatinine urine, lipid peroxidation kidneys measured. distribution expression levels inflammatory fibrotic mediators evaluated through immunohistochemistry (NOX4, CML, RAGE, nuclear NF-κB, TNF-α, IL-1β, TGF-β1, SMAD2/3, CTGF, a-SMA) immunolocalization CML/RAGE. Results: Glycoside flavonoid derivatives, such as patuletin spinacetin, primarily identified extract. Kidneys from group showed altered morphology, dead cells proximal tubules, increased oxidative stress markers; notably, these effects improved by SME treatment (STZ-SME). STZ-SME a lower staining intensity for CML which was decrease factors compared group. In all groups, markers varied among tubule, glomerular, interstitial cells. Conclusions: may help prevent or delay regulating processes AGEs/RAGE pathway, mechanism involved nephropathy.

Language: Английский

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Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation

Archives of Internal Medicine Research, Journal Year: 2024, Volume and Issue: 07(02)

Published: Jan. 1, 2024

The review delves into the methods for quantitative assessment of intracellular effectors and cellular response Receptor Advanced Glycation End products (RAGE), a vital transmembrane receptor involved in range physiological pathological processes. RAGE bind to (AGEs) other ligands, which turn activate diverse downstream signaling pathways that impact responses such as inflammation, oxidative stress, immune reactions. article discusses activated by followed differential activation across various diseases. This will ultimately guide researchers developing targeted effective interventions diseases associated with activation. Further, we have discussed how PCR, western blotting, microscopic examination molecules can be leveraged monitor, diagnose, explore involving proteins unique post-translational modifications. underscores pressing need advancements molecular approaches disease detection management RAGE.

Language: Английский

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