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

ABSTRACT: 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.

SUBMITTER: Cai X

PROVIDER: S-EPMC6749311 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Cai Xuan X Yang Fan F Zhu Lihui L Xia Ye Y Wu Qingyuan Q Xue Huiqin H Lu Yonghong Y

Molecules (Basel, Switzerland) 20190821 17

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 rosm ...[more]

PMID: 31438521

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Project description:BackgroundPancreatic cancer is one of the most notorious cancers and is known for its highly invasive characteristics, drug resistance, and metastatic progression. Unfortunately, many patients with advanced pancreatic cancer become insensitive towards gemcitabine treatment. Orthosiphon stamineus (O.s) is used widely as a traditional medicine for the treatment of multiple ailments, including cancer in South East Asia. The present in vitro study was designed to investigate the complementary effects of an ethanolic extract of O.s (Et. O.s) or rosmarinic acid in combination with gemcitabine on Panc-1 pancreatic cancer cells.MethodCell viability and colony formation assays were used to determine the 50% inhibitory concentration (IC50) of Et. O.s, rosmarinic acid, and gemcitabine. Different doses of gemcitabine in combination with Et. O.s or rosmarinic acid were tested against Panc-1 to select the best concentrations which possessed synergistic effects. Elucidation of molecular mechanisms responsible for mediating chemo-sensitivity in Panc-1 was performed using Quantitative Real-time PCR (QPCR), flow cytometry and immunohistochemistry.ResultsEt. O.s was found to significantly sensitise Panc-1 towards gemcitabine by reducing the gene expression of multidrug-resistant protein family (MDR) (MDR-1, MRP-4, and MRP-5) and molecules related to epithelial-mesenchymal transition (ZEB-1 and Snail-1). An induction of the human equilibrate nucleoside transporter-1 (hENT-1) gene was also found in cells treated with Et. O.s-gemcitabine. The Et. O.s-gemcitabine combination induced cellular senescence, cell death and cell cycle arrest in Panc-1. In addition, the inhibition of Notch signalling was demonstrated through the downregulation of Notch 1 intracellular domain in this treatment group. In contrast, rosmarinic acid-gemcitabine combination showed no additional effects on cellular senescence, apoptosis, epithelial mesenchymal transition (EMT) markers, the MRP-4 and MRP-5 multi-drug resistance protein family, hENT-1, and the Notch pathway through Notch 1 intracellular domain.ConclusionThis study provides valuable insights on the use of Et. O.s to complement gemcitabine in targeting pancreatic cancer in vitro, suggesting its potential use as a novel complementary treatment in pancreatic cancer patients.

Project description:BackgroundNephrolithiasis is a systemic metabolic disease with a high prevalence worldwide and is closely related to lipid-mediated oxidative stress and inflammation. Orthosiphon stamineus Benth. (OS) is a traditional medicinal herb mainly containing flavonoids, caffeic acid derivatives, and terpenoids, which has the effect of treating urinary stones. However, the active ingredients of OS for the treatment of kidney stones and their regulatory mechanisms remain unknown. As a powerful antioxidant, flavonoids from herbs can mitigate calcium oxalate stone formation by scavenging radical. Thus, this work focused on EtOAc extract of OS (EEOS, mainly flavonoids) and aimed to reveal the potential intrinsic mechanism of EEOS in the treatment of kidney stones disease.MethodsFirstly, 75% ethanol extract of OS was further extracted with EtOAc to obtain EtOAc extract containing 88.82% flavonoids. Secondly, the extract was subjected to component analysis and used in animal experiments. Then, an untargeted lipidomics based on ultrahigh performance liquid chromatography coupled with TripleTOF 5600 mass spectrometer (UPLC-QTOF-MS) was performed to test the lipid changes of kidneys in the control group, model group and EEOS treatment groups. Finally, multivariate statistical analysis was used to identify differences between the lipid profiles of mice in the model group and the EEOS group.ResultsFifty-one lipid metabolites were significantly different between the mice in the model group and the EEOS intervention group, including glycerophosphocholines, glycerophosphoethanolamines, glycerophosphoinositols, and glycerophosphoglycerols. And the composition of glycerophospholipids-esterified ω-3 polyunsaturated fatty acids and glycerophospholipid subclasses in the kidneys of the EEOS group significantly changed compared to model group.ConclusionsThe EEOS can inhibit the stones formation by improving oxidative stress and inflammation mediated by glycerophospholipid metabolism. This study reveals the potential mechanism of EEOS for kidney stones treatment at the lipid molecule level, providing a new direction for further study of the efficacy of OS.

Dataset Information

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

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

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