Phœnix dactylifera, L. seed oil alleviates Bleomycin-induced pulmonary fibrosis and oxidative stress in Wistar rats.

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is the most serious form of interstitial lung disease. We aimed to investigate the effect of Phœnix dactylifera, L. seed oil (DSO) on a murine model of IPF induced by bleomycin (BLM). METHODS: Male Wistar rats were treated with a single intra-tracheal injection of BLM (4 mg/kg) and a daily intraperitoneal injection of DSO (75, 150 and 300 mg/kg) for 4 weeks. RESULTS: Our phytochemical results showed that DSO has an important antioxidant activity with a high content of polyphenols and flavonoids. High-Performance Liquid Chromatography (HPLC) and Gas chromatography/mass spectrometry (GC-MS) analysis revealed a high amount of oleic and lauric acids and a large quantity of vitamins. Histological examination showed a significant reduction in fibrosis score and collagen bands in the group of rats treated with 75 mg/kg of DSO compared to the BLM group. DSO (75 mg/kg) reversed also the increase in catalase and malondialdehyde (MDA) levels while higher doses (150 and 300 mg/kg) are ineffective against the deleterious effects of BLM. We revealed also that DSO has no renal or hepatic cytotoxic effects. CONCLUSION: DSO can play antioxidant and antifibrotic effects on rat models of pulmonary fibrosis at the lowest dose administered.

Industrial Elimination of Essential Oils from Rosmarinus Officinalis: In Support of the Synergic Antifibrotic Effect of Rosmarinic and Carnosic Acids in Bleomycin Model of Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by collagen deposition as a consequence of excessive lung fibroblasts and myofibroblasts proliferation. We aimed to investigate for the first time the effect of rosemary leaf extract rich with carnosic acid (CA) or rosmarinic acid (RA), after industrial elimination of essential oils, against bleomycin (BLM)-induced lung fibrosis in rats. Male Wistar rats were given a single dose of BLM (4 mg/kg, intratracheal), while CA rich extract, RA rich extract or the combination RA/CA rich extracts (10, 75 and 150 mg/kg, intraperitoneal) were administered 3 day later and continued for 4 weeks. We reveled by HPLC an important similar amount of phenolic compounds such as pyrogallol, vanillic, gallic and ellagic acids in both rosemary extracts. BLM induced lung fibrotic foci and disturbance in superoxide dismutase, catalase and malondialdehyde levels. At 10 mg/kg, both rosemary extracts administrated alone or in combination alleviated synergistically lung fibrosis and ameliorated oxidative changes induced by BLM. In conclusion, industrial elimination of essential oils from rosemary allowed us to obtain two extracts with potent antifibrotic activities due to the large amount of RA and CA that appear much higher and effective than wild rosemary extract.

Comparison of the Protective Effect of Salvia officinalis and Rosmarinus officinalis Infusions Against Hepatic Damage Induced by Hypotermic-Ischemia in Wistar Rats.

We aimed to evaluate, in this study, the effect of Rosmarinus officinalis L. and Salvia officinalis L. in the amelioration of liver hypothermic conservation in male wistar rats. Livers from each rat were collected and preserved for 24 h at 4 °C in a Krebs solution with or without increasing doses of sage or rosemary infusions (25, 50, and 100 mg/mL). Liver hypothermic conservation induced a decrease in the activity of superoxide dismutase, catalase, and glutathione peroxidase and a significant increase in lipid peroxidation. S. officinalis L. infusion at 25 mg/mL normalized this oxidative disturbance but appears toxic at 50 and 100 mg/mL due to the presence of large amount of pyrogallol which contribute to the cytoplasmic alteration of hepatocytes. The addition of different doses of R. officinalis L. infusion induced an increase in catalase and glutathione peroxidase activities and a decrease in lipid peroxidation with an amelioration of cellular architecture. In conclusion, increasing doses of R. officinalis L. infusion protect against hepatic hypotermic-ischemia while S. officinalis L. infusion could have an hepatoprotective role when administrated at lower dose.

Salvia officinalis attenuates bleomycin-induced oxidative stress and lung fibrosis in rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive and irreversible fibroblasts proliferation leading to significant respiratory insufficiency. This study was designed to investigate the effect of sage infusion against bleomycin (BLM)-induced lung fibrosis in rats. Male Wistar rats were given a single dose of BLM (4 mg/kg, intratracheal), while sage infusion (50, 100 and 150 mg/kg, intraperitoneal) was administered 3 day later and continued for 4 weeks. We reveled by HPLC and LC-MS methods an important amount of phenolic bioactive compounds such as vanillic, gallic, ellagic, rosmarinic and carnosic acids. BLM induced collagen deposition, increased lipid peroxidation (MDA) and decreased superoxide dismutase (SOD) and catalase (CAT) activities. Only sage infusion at 150 mg/kg normalized MDA and antioxidant enzyme levels (SOD and CAT) and reduced significantly lung fibrosis. Our results showed also that this high dose have no renal or hepatic cytotoxic effect. In conclusion, sage can protect against BLM-induced murine lung fibrosis and oxidative stress due to the large content of bioactive phenolic compounds.

Protective role of vitamin E against cadmium induced oxidative stress into the rat liver.

INTRODUCTION: Cadmium (Cd) is a toxic heavy metal used in various industrial applications and therefore can cause, both by environmental or professional exposure, several damage in all body systems. The present study was developed to determine the toxic effect of high dose of Cd on the rat's liver as well as the putative protective effect of vitamin E. METHODS: During the experiment, rats were administrated Cd per orally (PO) (15mg/Kg bw) alone or associated with an intraperitonial (IP) injection of alphatocopherol (Vitamin E) (300mg/Kg / day) for three weeks. We analyzed the effect of vitamin E on Cd induced liver remodeling by hematoxylin-eosin staining (HE), and by the determination of the antioxidant profiles and lipid peroxidation in rats's livers. RESULTS: Data confirmed that high dose of cd induced a loss of the liver weight and a pro-oxidative state into hepatocytes characterized by increased malondialdehyde (MDA) and peroxidase (POD), no changes in catalase (CAT) and a decrease on the superoxide dismutase (SOD) activities. These disturbances may be explained by a decrease in the level of hepatic calcium (Ca). Co-treatment with Vitamin E, decreased MDA and POD activities, increased CAT and SOD activities and restored Ca level. All these corrections were accompanied by an improvement of the liver 's structure. CONCLUSION: Our results suggest that Cd induced an oxidative stress into rat liver and Vitamin E exerted antioxidant properties which can be mediated by the modulation of Ca level.

Effect of Phoenix dactylifera L. Sap Against Bleomycin-Induced Pulmonary Fibrosis and Oxidative Stress in Rats: Phytochemical and Therapeutic Assessment.

Lung fibrosis is a lethal interstitial disease characterized by massive proliferation of fibroblast inducing excessive collagen deposition. We aimed to investigate whether Date palm sap (DPS) can play a protective effect on bleomycin (BLM)-induced lung fibrosis in rats. MaleWistar rats were given single dose of BLM (4 mg/kg, intra-tracheal), while DPS (45 mg/kg, intraperitoneal) was administered three days later and continued for three weeks (BLM/DPS group). Characterization of phenolic compounds in DPS was evaluated by LC-HRESIMS analysis. Hematoxylin-eosin and Masson's Trichome staining were used for the revelation of lung architecture, collagen deposition, and fibrosis score. Antioxidant effects of DPS and hydroxyproline content in lung tissues were studied using standard spectrophotometric methods. We reveled by liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC-HRESIMS) an important amount of vitamins and phenolic compounds in DPS. BLM increased lipid peroxidation (MDA) and superoxide dismutase (SOD) levels and decreased catalase (CAT) activity. BLM also induced inflammation and accumulation of bundles of collagen in lung. DPS treatment normalized MDA, SOD, and CAT levels, decreased hydroxyproline level and morphological lesions induced by BLM. In conclusion, DPS has a protective effect against BLM-induced murine lung fibrosis due to its richness in phenolic compounds and vitamins.

Rosmarinic acid potentiates carnosic acid induced apoptosis in lung fibroblasts.

Pulmonary fibrosis is characterized by over-population and excessive activation of fibroblasts and myofibroblasts disrupting normal lung structure and functioning. Rosemary extract rich in carnosic acid (CA) and rosmarinic acid (RA) was reported to cure bleomycin-(BLM)-induced pulmonary fibrosis. We demonstrate that CA decreased human lung fibroblast (HLF) viability with IC50 value of 17.13±1.06 µM, while RA had no cytotoxic effect. In the presence of 50 µM of RA, dose-response for CA shifted to IC50 value of 11.70±1.46 µM, indicating synergic action. TGFß-transformed HLF, rat lung fibroblasts and L929 cells presented similar sensitivity to CA and CA+RA (20µM+100µM, respectively) treatment. Rat alveolar epithelial cells died only under CA+RA treatment, while A549 cells were not affected. Annexin V staining and DNA quantification suggested that HLF are arrested in G0/G1 cell cycle phase and undergo apoptosis. CA caused sustained activation of phospho-Akt and phospho-p38 expression and inhibition of p21 protein.Addition of RA potentiated these effects, while RA added alone had no action.Only triple combination of inhibitors (MAPK-p38, pan-caspase, PI3K/Akt/autophagy) partially attenuated apoptosis; this suggests that cytotoxicity of CA+RA treatment has a complex mechanism involving several parallel signaling pathways. The in vivo antifibrotic effect of CA and RA was compared with that of Vitamine-E in BLM-induced fibrosis model in rats. We found comparable reduction in fibrosis score by CA, RA and CA+RA, attenuation of collagen deposition and normalization of oxidative stress markers. In conclusion, antifibrotic effect of CA+RA is due to synergistic pro-apoptotic action on lung fibroblasts and myofibroblasts.

The efficacy of plant extract and bioactive compounds approaches in the treatment of pulmonary fibrosis: A systematic review.

Pulmonary fibrosis (PF) is a lethal, chronic and progressive respiratory disease leading to interstitial lung damage and serious breathing problems. The pathogenic mechanism involves activation, migration, proliferation and differentiation of fibroblasts into myofibroblats inducing extracellular matrix accumulation that destroy lung parenchyma. Available antifibrotic treatment options are limited to Pirfenidone and Nintedanib that prevent deterioration without an improvement of this disease. The use of plant extracts and natural bioactive compounds for the treatment of PF has been known for more than thirty years in China. Nowadays, phytotherapy has gained a considerable attention in the treatment of PF both in vivo and in vitro using bleomycin (BLM)-induced lung inflammation, oxidative stress and pulmonary fibrosis in rats. In this review, we aimed to focus on the protective effects and the mechanisms of action of several plant extracts described by various research works for the treatment of PF.

Prophylactic and curative effect of rosemary leaves extract in a bleomycin model of pulmonary fibrosis.

CONTEXT: Pulmonary fibrosis is a devastating disease without effective treatment. Rosemary is appreciated since ancient times for its medicinal properties, while biomolecules originated from the plant have an antioxidant and antifibrotic effect. OBJECTIVE: The effects of Rosmarinus officinalis L. (Lamiaceae) leaves extract (RO) on bleomycin-induced lung fibrosis were investigated. MATERIALS AND METHODS: Male Wistar rats were given a single dose of bleomycin (BLM, 4 mg/kg, intratracheal), while RO (75 mg/kg, intraperitoneal) was administered 3 days later and continued for 4 weeks (BLM/RO1-curative group). Alternatively, RO was administered 2 weeks before BLM and continued 15 days thereafter (BLM/RO2-prophylactic group). Antioxidant activities of RO and lung tissues were studied by standard methods. Histological staining revealed lung architecture and collagen deposition. RO was characterized for its polyphenol content and by high-performance liquid chromatography. RESULTS: RO polyphenol content was 60.52 mg/g of dry weight, carnosic and rosmarinic acids being major components (6.886 and 2.351 mg/g). Antioxidant effect of RO (DPPH and FRAP assay) expressed as IC50 values were 2.23 µg/mL and 0.074 µg/mL, respectively. In BLM/RO1 and BLM/RO2 lung architecture was less compromised compared to BLM, which was reflected in lower fibrosis score (2.33 ± 0.33 and 1.8 ± 0.32 vs 3.7 ± 0.3). Malondialdehyde levels were attenuated (141% and 108% vs 258% of normal value). Catalase and glutathione-S-transferase activities were normalized (103% and 117% vs 59%, 85% and 69% vs 23%, respectively). DISCUSSION AND CONCLUSION: RO has a protective effect against BLM-induced oxidative stress and lung fibrosis due to its phenolic compounds.

Relevance of carnosic acid to the treatment of several health disorders: Molecular targets and mechanisms.

Carnosic acid is a phenolic diterperne compound found in abundance in sage and rosemary, which are both widely used in traditional medicine. Research over the past decade indicates that carnosic acid has multiple bioactive properties including antioxidant, anti-inflammatory and anticancer activities among others. This review summarizes the current in vitro and in vivo data about the efficacy of carnosic acid in the prevention or treatment of various experimental health disorders. The analysis of the literature allows an insight into the participation of numerous signaling pathways modulated by carnosic acid, into its synergistic potential and, thus, into the divergence in cellular mechanisms of action of this molecule.