Rosmarinic Acid, the Main Effective Constituent of Orthosiphon stamineus, Inhibits Intestinal Epithelial Apoptosis Via Regulation of the Nrf2 Pathway in Mice

Many studies have shown that Orthosiphon stamineus extract (OE) has antioxidant activity, and we previously reported that OE protects the intestine against injury from a high-fat diet. However, the molecular mechanism underlying this protective effect of OE was unclear. Here, OE was separated according to polarity and molecular weight, and the antioxidant activity of each component was compared. The components with the highest antioxidant activity were analyzed by HPLC, which confirmed that rosmarinic acid (RA) was the main effective constituent in OE. OE and RA were then tested in a mouse high-fat diet-induced intestinal injury model. The antioxidant indices and morphological characteristics of the mouse jejunum were measured, and activation of the nuclear factor E2-related factor 2 (Nrf2) pathway and apoptosis of jejunal epithelial cells were analyzed. Of all the constituents in OE, RA contributed the most. Both RA and OE activated the Nrf2 pathway and increased downstream antioxidant enzyme activity. RA and OE protected the mouse intestine against high-fat diet-induced oxidative stress by preventing intestinal epithelial cell apoptosis via both extracellular and intracellular pathways. Thus, RA, the main effective constituent in OE, inhibits intestinal epithelial apoptosis by regulating the Nrf2 pathway in mice.

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Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00311.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E180-E195 ◽

Cited By ~ 14

Author(s):

Dionysios V. Chartoumpekis ◽

Dushani L. Palliyaguru ◽

Nobunao Wakabayashi ◽

Marco Fazzari ◽

Nicholas K. H. Khoo ◽

...

Keyword(s):

High Fat Diet ◽

Whole Body ◽

Related Factor ◽

High Fat ◽

Nonesterified Fatty Acids ◽

Nrf2 Pathway ◽

Diet Induced Obesity ◽

Triglyceride Accumulation ◽

Nrf2 Knockout ◽

Obesity In Mice

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a canonical regulator of cytoprotective gene expression, but evidence of its cross talk with other pathways, including metabolic ones, is ever increasing. Pharmacologic or systemic genetic activation of the Nrf2 pathway partially protects from obesity in mice and ameliorates fasting hyperglycemia in mice and humans. However, systemic Nrf2 deletion also protects from diet-induced obesity and insulin resistance in mice. To further investigate the effect of the disruption of Nrf2 on obesity in a tissue-specific manner, we focused on adipocytes and hepatocytes with targeted deletion of Nrf2. To this end, mice with cell-specific deletion of Nrf2 in adipocytes (ANKO) or hepatocytes (HeNKO) were fed a high-fat diet (HFD) for 6 mo and showed similar increases in body weight and body fat content. ANKO mice showed a partially deteriorated glucose tolerance, higher fasting glucose levels, and higher levels of cholesterol and nonesterified fatty acids compared with their Control counterparts. The HeNKO mice, though, had lower insulin levels and trended toward improved insulin sensitivity without having any difference in liver triglyceride accumulation. This study compared for the first time two conditional Nrf2 knockout models in adipocytes and in hepatocytes during HFD-induced obesity. None of these models could completely recapitulate the unexpected protection against obesity observed in the whole body Nrf2 knockout mice, but this study points out the differential roles that Nrf2 may play, beyond cytoprotection, in different target tissues and rather suggests systemic activation of the Nrf2 pathway as an effective means of prevention and treatment of obesity and type 2 diabetes.

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Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2015.11.040 ◽

2016 ◽

Vol 591 ◽

pp. 57-65 ◽

Cited By ~ 41

Author(s):

Stephen L. Slocum ◽

John J. Skoko ◽

Nobunao Wakabayashi ◽

Susan Aja ◽

Masayuki Yamamoto ◽

...

Keyword(s):

High Fat Diet ◽

High Fat ◽

Nrf2 Pathway ◽

Pathway Activation

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Involvement of Nuclear Related Factor 2 Signaling Pathway in the Brain of Obese Rats and Obesity-Resistant Rats Induced by High-Fat Diet

Journal of Medicinal Food ◽

10.1089/jmf.2015.3500 ◽

2016 ◽

Vol 19 (4) ◽

pp. 404-409 ◽

Cited By ~ 2

Author(s):

Wei-Wei Ma ◽

Bing-Jie Ding ◽

Li-Jing Wang ◽

Yi Shao ◽

Rong Xiao

Keyword(s):

Signaling Pathway ◽

High Fat Diet ◽

Related Factor ◽

High Fat ◽

Obese Rats ◽

The Brain

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3 INTESTINAL EPITHELIAL RECEPTOR LRRC19 DEPLETION PROTECTS MATERNAL HIGH FAT DIET-INDUCED GUT BARRIER DISRUPTION OF OFFSPRING

Gastroenterology ◽

10.1016/s0016-5085(20)30684-3 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-1-S-2

Author(s):

Shumin Huang ◽

Runxiang Xie ◽

Huan Huang ◽

Tianyu Liu ◽

Hailong Cao

Keyword(s):

High Fat Diet ◽

Intestinal Epithelial ◽

High Fat ◽

Gut Barrier ◽

Barrier Disruption

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Protective Effects of Eicosapentaenoic Acid Plus Hydroxytyrosol Supplementation Against White Adipose Tissue Abnormalities in Mice Fed a High-Fat Diet

Molecules ◽

10.3390/molecules25194433 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4433

Author(s):

Paola Illesca ◽

Rodrigo Valenzuela ◽

Alejandra Espinosa ◽

Francisca Echeverría ◽

Sandra Soto-Alarcon ◽

...

Keyword(s):

Adipose Tissue ◽

Eicosapentaenoic Acid ◽

White Adipose Tissue ◽

High Fat Diet ◽

Enzyme Linked Immunosorbent Assay ◽

Related Factor ◽

Nuclear Factor ◽

High Fat ◽

Mitochondrial Energy Metabolism ◽

Ppar Γ

Objective: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations. Methods: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks. Determinations in WAT include morphological parameters, EPA and docosahexaenoic acid content in phospholipids (gas chromatography), lipogenesis, oxidative stress (OS) and inflammation markers, and gene expression and activities of transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma (PPAR-γ), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (p65 subunit) and nuclear factor erythroid 2-related factor 2 (Nrf2) (quantitative polymerase chain reaction and enzyme linked immunosorbent assay). Results: HFD led to WAT hypertrophy in relation to PPAR-γ downregulation. WAT metabolic dysfunction was characterized by upregulation of lipogenic SREBP-1c system, mitochondrial energy metabolism depression, loss of the antioxidant Nrf2 signaling with OS enhancement, n-3 long-chain polyunsaturated fatty acids depletion and activation of the pro-inflammatory NF-κB system. EPA and HT co-supplementation diminished HFD-dependent effects additively, reaching values close or similar to controls. Conclusion: Data presented strengthen the importance of combined protocols such as EPA plus HT to attenuate metabolic-inflammatory states triggered by obesity.

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