Interruptins A and B exhibited anti-diabetic, anti-inflammatory, and anti-oxidative effects. This study aimed to investigate the therapeutic ability of extract enriched by interruptins A and B (EEI) from an edible fern Cyclosorus terminans on insulin resistance and non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-induced obese rats and elucidate their possible mechanisms. HFD-induced obese rats were treated with EEI for 2 weeks. Real-time polymerase chain reaction (PCR) was used to examine the molecular basis. We found that EEI supplementation significantly attenuated body and liver weight gain, glucose intolerance, and insulin resistance. Concurrently, EEI increased liver and soleus muscle glycogen storage and serum high-density lipoprotein (HDL) levels. EEI also attenuated NAFLD, as indicated by improving liver function. These effects were associated with enhanced expression of insulin signaling genes (Slc2a2, Slc2a4, Irs1 and Irs2) along with diminished expression of inflammatory genes (Il6 and Tnf). Furthermore, EEI led to the suppression of lipogenesis genes, Srebf1 and Fasn, together with an increase in fatty acid oxidation genes, Ppara and Cpt2, in the liver. These findings suggest that EEI could ameliorate HFD-induced insulin resistance and NAFLD via improving insulin signaling pathways, inflammatory response, lipogenesis, and fatty acid oxidation.
Context: Interruptins A and B derivatives from edible fern Cyclosorus terminans have been reported properties including anti-bacterial, anti-cancer, anti-oxidation, anti-inflammatory, and antidiabetic activities. Unfortunately, studies on its safety are still scarce. Aims: To evaluate the acute oral toxicity of interruptin-rich extract (IRE) from C. terminans in Wistar rats and examine the antidiabetic potential of IRE in vitro. Methods: IRE was evaluated cytotoxicity by MTT assay and potency of glucose consumption in hepatocyte and skeletal muscle cells. IRE was evaluated for acute toxicity in Wistar rats by following OECD 420 guidelines. Wistar rats were single oral administrated of 2000 mg/kg IRE and further observed for 14 days. LCMS was assessed for verifying IRE absorption into the bloodstream. Hematological, biochemical parameters and microscopic examination of heart, liver and kidney were evaluated. Results: IRE demonstrated no cytotoxicity toward hepatocytes and skeletal muscle cells and facilitated glucose consumption into cells. In the acute toxicity study, on day 14, after a single oral administration of 2000 mg/kg IRE, no mortality and behavioral alterations. There was no change in metabolic parameters. Histopathology of heart, liver and kidney showed normal architecture. Conclusions: Thus, LD50 of IRE was considered superior to 2000 mg/kg. Hence the extract can be utilized safely and could provide a capability for diabetic control.
Background Long‐term high‐fat diet consumption causes prediabetic conditions with brain pathology, as indicated by peripheral and brain insulin resistance, neuroinflammation, neuronal necroptosis, microglial and astrocyte hyperactivation and increased Alzheimer’s disease‐related proteins including amyloid precursor protein (APP). Although pioglitazone, a peroxisome proliferator‐activated receptor (PPAR)‐γ agonist clinically used to treat type 2 diabetes mellitus, has been shown to improve the metabolic and brain functions in prediabetic condition, this drug can lead to several adverse effects. Recently, an in vitro study showed that Cyclosorus terminans extract, which acts as a natural PPAR‐γ agonist, possessed anti‐diabetic and anti‐obesity properties in adipose‐derived stem cells. However, the comparative efficacy of Cyclosorus terminans extract and pioglitazone on metabolic and brain functions in the prediabetic model has not been elucidated. Method Thirty male rats were fed with either a normal diet (ND) or a high‐fat diet (HFD) for 14 weeks. At week 13, ND‐fed rats received vehicle (NDV; n = 6) for additional 2 weeks. HFD‐fed rats were divided into four subgroups to receive either vehicle (HFV; n = 6), 100 mg/kg/day of Cyclosorus terminans extract (I‐100; n = 6), 200 mg/kg/day of Cyclosorus terminans extract (I‐200; n = 6); or 20 mg/kg/day of pioglitazone (Pio; n = 6) for additional 2 weeks. At the end of experimental period, blood and brains were collected to determine metabolic and brain functions. Result HFD‐fed rats exhibited a prediabetic condition as characterized by obesity with peripheral insulin resistance. In addition, neuroinflammation, neuronal necroptosis, microglial and astrocyte hyperactivation, and APP expression significantly increased in HFD‐induced prediabetic rats. Cyclosorus terminans extract (100 mg/kg/day) did not attenuate the metabolic disturbance and brain pathologies in HFD‐induced prediabetic rats. Interestingly, 200 mg/kg/day of Cyclosorus terminans extract and pioglitazone equally attenuated peripheral insulin resistance, neuroinflammation, neuronal necroptosis, microglial and astrocyte hyperactivation, and APP expression in HFD‐induced prediabetic rats (P < 0.05, Figure 1). Conclusion These findings suggest that Cyclosorus terminans extract may be another therapeutic approach for improving metabolic and brain functions in prediabetic patients who have contraindications to pioglitazone therapy.
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