Dapagliflozin prevents reproductive damage caused by acute systemic inflammation through antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Dapagliflozin (DPG) is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that has been suggested to possess anti-inflammatory properties in diabetes. The aim of this study is to evaluate the role of DPG administration in preventing lipopolysaccharide (LPS)-induced damage in the female genital system. Thirty-two female Wistar Albino rats were randomly allocated into four groups: control group, LPS group, LPS + DPG group and DPG group. At the end of the experimental phase, ovary, fallopian tube and uterus tissues were collected for histopathological, immunohistochemical, genetic and biochemical analyses. The findings showed that LPS caused histopathological changes characterized by marked hyperaemia, mild to moderate haemorrhage, oedema and neutrophil leucocyte infiltrations and degenerative and necrotic changes in the female genital tract. In addition, it decreased total antioxidant status (TAS), increased total oxidant status (TOS) and oxidative stress index (OSI) levels. LPS also increased the expressions of Cas-3, G-CSF and IL-1β in the ovary, fallopian tubes and uterus immunohistochemically. While Claudin-1 expression decreased, NLRP3 and AQP4 gene expressions increased due to LPS. However, DPG treatment prevented all these changes. The results of this study indicate that, DPG can be used to prevent LPS-induced lesions in the female reproductive system.

Topsakal S ，Ozmen O ，Asci H ，Gulal A ，Ozcan KN ，Aydin B ... -  《-》

The dynamic interplay between AMPK/NFκB signaling and NLRP3 is a new therapeutic target in inflammation: Emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury.

Acute lung injury (ALI) is one the most common causes of morbidity and mortality in critically ill patients. In this study, we examined for first time the role of dapagliflozin (DPGZ) in lipopolysaccharide (LPS)-induced ALI in rats and determined the underlying molecular mechanisms by evaluating the effects of DPGZ on adenosine monophosphate kinase (AMPK), nuclear transcription factor kappa B, nucleotide-binding and oligomerization domain-like receptor 3 inflammasome activation. Treatment of acute lung injured rats with either low dose (5 mg/kg) or high dose (10 mg/kg) DPGZ significantly decreased oxidative stress by decreasing malondialdehyde and nitric oxide tissue levels with a significant increase in spectrophotometric measurements of superoxide dismutase, catalase, and reduced glutathione levels. DPGZ treatment resulted in a significant anti-inflammatory effect as indicated by suppression in myeloperoxidase activity, MCP-1, IL-1β, IL-18, and TNF-α levels. DPGZ treatment also increased p-AMPK/t-AMPK with a significant reduction in NF-kB P65 binding activity and NFĸB p65 (pSer536) levels. These effects of DPGZ were accompanied by a significant reduction in NLRP3 levels and NLRP3 gene expression and a significant decrease in caspase-1 activity, which were also confirmed by histopathological examinations. We conclude that DPGZ antioxidant and anti-inflammatory activity may occur through regulation of AMPK/NFĸB pathway and inhibition of NLRP3 activation. These results suggest that DPGZ represents a promising intervention for the treatment of ALI, particularly in patients with type 2 diabetes.

Abd El-Fattah EE ，Saber S ，Mourad AAE ，El-Ahwany E ，Amin NA ，Cavalu S ，Yahya G ，Saad AS ，Alsharidah M ，Shata A ，Sami HM ，Kaddah MMY ，Ghanim AMH ... -  《-》

Empagliflozin protective effects against cisplatin-induced acute nephrotoxicity by interfering with oxidative stress and inflammation in Wistar rats.

Cisplatin (Cis) is a platinum-based antineoplastic drug used in various types of cancers. This drug can induce nephrotoxicity as a cause of acute kidney injury (AKI) by inducing oxidative stress and inflammation. Empagliflozin (Empa) is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. In addition to its blood glucose-lowering effect, Empa has been shown to exert anti-inflammatory and anti-oxidant properties. The current study aimed to investigate the protective effects of Empa on Cis-induced nephrotoxicity in rats. Male Wistar albino rats were divided into five groups, each of six rats: Sham group (received vehicle for 7 days), Control group (received vehicle for 7 days and Cis injection on day 2), Cis + Empa10 (received 10mg/kg Empa for 7 days and Cis injection on day 2), Cis + Empa30 (received 30mg/kg Empa for 7 days and Cis injection on day 2) and, Empa 30 (received 30mg/kg Empa for 7 days). One day after the last injection in each group, rats were weighed and then sacrificed to analyze the hematological, biochemical, and histological parameters. Cis markedly increased levels of inflammatory parameters such as renal tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and myeloperoxidase (MPO) activity. Notably, malondialdehyde (MDA), blood urea nitrogen (BUN), and creatinine levels were enhanced after Cis administration. Also, the chemotherapeutic agent significantly reduced antioxidant indicators such as renal catalase (CAT), glutathione peroxidase (GpX), and superoxide dismutase (SOD). Furthermore, histopathological examinations also revealed severe renal damage following Cis treatment which was improved by Empa administration. Empa treatment at both doses (10 mg/kg and 30 mg/kg) reversed Cis-induced changes in all the above renal parameters. In conclusion, Empa has protective effects on Cis-induced nephrotoxicity by inhibition of oxidative stress and inflammation.

Farrokh-Eslamlou N ，Momtaz S ，Niknejad A ，Hosseini Y ，Mahdaviani P ，Ghasemnejad-Berenji M ，Abdolghaffari AH ... -  《-》

Dapagliflozin improves steatohepatitis in diabetic rats via inhibition of oxidative stress and inflammation.

Type-2 diabetes mellitus and NAFLD are considered as one of the greatest worldwide metabolic disorders with growing incidence. It was found that patients with T2DM have two-fold increase to develop NAFLD. Evidence that some antidiabetic agents improve NAFLD/NASH in patients with T2DM is evolving. However, there are no certain pharmacologic therapies. The current study aimed to investigate the underlying mechanisms for the hepatoprotective effect of dapagliflozin against steatohepatitis in diabetic rats. Type-2 diabetes was induced by HFD followed by a single dose of STZ (30 mg/kg I.P). Fifty rats were randomly divided into 5 groups: Group1; normal control, Group 2; diabetic control, Groups (3-5); diabetic rats received daily dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.) respectively for 6 weeks. At the end of the experiment, blood glucose level and serum insulin were measured. Hepatic tissue homogenization was performed for measuring inflammatory and oxidative stress markers. In addition, histopathological investigation of the hepatic tissue was done. Diabetic rats exhibited remarkable increase in liver weight and liver enzymes, along with histopathological changes, significant elevation in MDA, IL-1 β, TGFβ levels and, NF-κB, alpha-SMA expressions. Dapagliflozin treatment decreased liver weight, liver enzymes, together with marked improvement in histopathological changes. Furthermore, dapagliflozin increased antioxidant enzymes, GSH levels. Interestingly, Dapagliflozin reduced IL-1 β, TGFβ levels and, NF-κB, alpha-SMA expressions. Present data show that dapagliflozin represent a viable approach to protect the liver against diabetes-encouraged steatohepatitis through inhibiting oxidative stress, inflammation and fibrosis progression thus conserving liver function.

Hazem RM ，Ibrahim AZ ，Ali DA ，Moustafa YM ... -  《-》

Agomelatine could prevent brain and cerebellum injury against LPS-induced neuroinflammation in rats.

Sepsis, systemic hyper-inflammatory immune response, causes the increase of morbidity and mortality rates due to multi-organ diseases such as neurotoxicity. Lipopolysaccharide (LPS) induces inflammation, oxidative stress and apoptosis to cause brain damage. We aimed to evaluate the antioxidant, anti-inflammatory and antiapoptotic effects of Agomelatine (AGM) on LPS induced brain damage via NF-kB signaling. Twenty-four animals were divided into three groups as control, LPS (5 mg/kg) and LPS + AGM (20 mg/kg). Six hours after the all administrations, rats were sacrificed, brain tissues were collected for biochemical, histopathological and immunohistochemical analysis. In LPS group; total oxidant status (TOS), OSI index, Caspase-8 (Cas-8), NF-kß levels increased and Total antioxidant status (TAS) levels decreased biochemically and Cas-8, haptoglobin and IL-10 expressions increased and sirtuin-1 (SIRT-1) levels decreased immunohistochemically. AGM treatment reversed these parameters except haptoglobin levels in hippocampus and SIRT-1 levels in cerebellum. Besides, AGM treatment blocked the phosphorylation of NF-kB biochemically and ameliorated increased the levels of hyperemia, edema and degenerative changes histopathologically. In conclusion, AGM enhanced SIRT-1 levels to negatively regulate the transcription and activation of p-NF-kB/p65 which caused to ameliorate inflammation, oxidative stress and apoptosis.

Savran M ，Aslankoc R ，Ozmen O ，Erzurumlu Y ，Savas HB ，Temel EN ，Kosar PA ，Boztepe S ... -  《-》