Potential anti-inflammatory effect of dapagliflozin in HCHF diet- induced fatty liver degeneration through inhibition of TNF-α, IL-1β, and IL-18 in rat liver

ElMahdy, Mohammed Kh.; Helal, Manar G.; Ebrahim, Tarek M.

doi:10.1016/j.intimp.2020.106730

Cited by 44 publications

(16 citation statements)

References 36 publications

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“…Animal studies showed enhancing hepatic AMP-activated protein kinase activity, thereby reduction of de novo lipogenesis 6 by dapagliflozin. The reduction of liver inflammation [5][6][7] and increased insulin sensitivity 6 are also potential mechanisms demonstrated in the preclinical studies.…”

Section: Discussionmentioning

confidence: 95%

“…4 Dapagliflozin, a highly selective SGLT2i, has been shown in animal studies to be able to improve steatohepatitis in rat with NAFLD model. [5][6][7] The potential mechanisms associated with hepatic steatosis alleviation involve the enhancing of hepatic AMP-activated protein kinase expression and activity, 6 reduction in hepatic inflammatory cytokines, [5][6][7] and oxidative stress, 6,7 and an increase in insulin sensitivity. 6 Clinical studies have demonstrated that dapagliflozin is effective in glycemic control, 8 and reduction in bodyweight, 8 visceral fat, and subcutaneous fat thickness.…”

Section: Introductionmentioning

confidence: 99%

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The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non‐alcoholic fatty liver disease

Phrueksotsai

Pinyopornpanish

Euathrongchit

et al. 2021

J of Gastro and Hepatol

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Background and Aim: Sodium-glucose cotransporter 2 inhibitors have shown excellent results in glucose control in type 2 diabetes mellitus (T2DM) patients, while also promoting weight loss. These mechanisms may be beneficial in the treatment of non-alcoholic fatty liver disease (NAFLD). Our study aims to investigate the effect of dapagliflozin on hepatic and visceral fat contents and related biochemical markers in T2DM with NAFLD patients. Methods: This is a double-blinded placebo-controlled randomized, single-center study. Non-insulin-dependent T2DM patients with NAFLD were prospectively enrolled and randomly assigned to receive either dapagliflozin (10 mg/day) or placebo for 12 weeks. The primary end-point was the changes in intrahepatic lipid contents, evaluated by the liver attenuation index. Results: Of 40 patients enrolled, 38 patients completed the study (dapagliflozin group, n = 18; placebo group, n = 20). Baseline demographic and laboratory findings were similar in both groups. After 12 weeks of treatment, dapagliflozin significantly decreased intrahepatic lipid contents demonstrated by an increase in liver attenuation index in comparison with the placebo treatment (5.8 ± 5.1 vs 0.5 ± 6.1 Hounsfield units, P = 0.006). Significant reduction in bodyweight, bodyfat, visceral fat/subcutaneous fat ratio, hemoglobin A1c, and alanine aminotransferase were also observed in the dapagliflozin-treated group as compared with the placebo group (all P < 0.05). There was no significant difference in adipokines including adiponectin, leptin, and tumor necrosis factor-α changes between the dapagliflozin-treated group and the placebo group (all P = nonsignificant). Conclusion: Dapagliflozin treatment for 12 weeks is associated with improvement in hepatic fat content, a decrease in visceral fat and bodyweight, enhanced glycemic control, and improved liver biochemistry among T2DM patients with NAFLD.* P < 0.05, comparison of baseline and post-treatment data within groups.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non‐alcoholic fatty liver disease

Phrueksotsai

Pinyopornpanish

Euathrongchit

et al. 2021

J of Gastro and Hepatol

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“…Dapagliflozin was shown to prevent the development of an atherogenic lipid profile and decrease the amount of MDA, interleukins 1β and 18 as well as TNFα in liver homogenates obtained from rats fed with a high carbohydrate diet. Dapagliflozin not only prevented the increase in all mentioned biomarkers in the liver tissue but also ameliorated histological lesions typical for NAFLD [ 54 ]. Intriguingly, dapagliflozin was also able to protect the liver from alcohol-triggered damage.…”

Section: Sglt2i As Antioxidative and Anti-inflammatory Agents In Tissues And Organs Other Than The Kidneymentioning

confidence: 99%

“…Liver: reduced oxidative stress by means of decreased level of MDA and sustained enzymatic activity of superoxide dismutase [ 54 , 58 ]…”

Section: Figurementioning

confidence: 99%

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

Winiarska

Knysak

Nabrdalik

et al. 2021

IJMS

110

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The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

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“…Dapagli ozin (DAPA; 10 mg tablets; AstraZeneca, Maryland, USA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has been con rmed to have renoprotective and anti-in ammatory effects in diabetes mellitus models [19,20], was used as a positive control.…”

Section: Drugs and Reagentsmentioning

confidence: 99%

Network pharmacology analysis of ZiShenWan for diabetic nephropathy and experimental verification of its anti-inflammatory mechanism

Guo

Chengfei

et al. 2020

Preprint

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Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The inflammatory response plays a critical role in the process of DN. ZiShenWan (ZSW) is a classical Chinese medicinal formula with remarkable clinical therapeutic effects on DN, but its pharmacological action mechanisms remain unclear. Methods: In this study, a network pharmacology approach was applied to investigate the pharmacological mechanism of ZSW in DN therapy. The “drug-ingredient-target” network for ZSW in DN treatment was established with Cytoscape software based on candidate active components of ZSW and targets in DN treatment obtained from databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed with the key targets. Because inflammation is important in DN, the key targets and signaling pathways associated with the anti-inflammatory, renoprotective mechanism of ZSW were partially validated in db/db mice. Results: A total of 56 active ingredients in ZSW and 166 DN-related targets were selected from databases. Various related genes and pathways participate in the inflammatory response. ZSW markedly alleviated renal injury in db/db mice by inhibiting the exaggerated release of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor -ɑ (TNF-ɑ), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1) and regulating the p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathways. Conclusions: Network pharmacology analysis demonstrated that ZSW achieved therapeutic renoprotective effects in DN by alleviating the inflammatory response via regulation of multiple targets and signaling pathways.

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Potential anti-inflammatory effect of dapagliflozin in HCHF diet- induced fatty liver degeneration through inhibition of TNF-α, IL-1β, and IL-18 in rat liver

Cited by 44 publications

References 36 publications

The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non‐alcoholic fatty liver disease

The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non‐alcoholic fatty liver disease

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

Network pharmacology analysis of ZiShenWan for diabetic nephropathy and experimental verification of its anti-inflammatory mechanism

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