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Aqueous Date Flesh or Pits Extract Attenuates Liver Fibrosis via Suppression of Hepatic Stellate Cell Activation and Reduction of Inflammatory Cytokines, Transforming Growth Factor- β 1 and Angiogenic Markers in Carbon Tetrachloride-Intoxicated Rats.

Al-Rasheed NM, Attia HA, Mohamad RA, Al-Rasheed NM, Al-Amin MA, Al-Onazi A - Evid Based Complement Alternat Med (2015)

Bottom Line: Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31.We concluded that DFE or DPE could protect liver via different mechanisms.The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia.

ABSTRACT
Previous data indicated the protective effect of date fruit extract on oxidative damage in rat liver. However, the hepatoprotective effects via other mechanisms have not been investigated. This study was performed to evaluate the antifibrotic effect of date flesh extract (DFE) or date pits extract (DPE) via inactivation of hepatic stellate cells (HSCs), reducing the levels of inflammatory, fibrotic and angiogenic markers. Coffee was used as reference hepatoprotective agent. Liver fibrosis was induced by injection of CCl4 (0.4 mL/kg) three times weekly for 8 weeks. DFE, DPE (6 mL/kg), coffee (300 mg/kg), and combination of coffee + DFE and coffee + DPE were given to CCl4-intoxicated rats daily for 8 weeks. DFE, DPE, and their combination with coffee attenuated the elevated levels of inflammatory cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-1β. The increased levels of transforming growth factor-β1 and collagen deposition in injured liver were alleviated by both extracts. CCl4-induced expression of α-smooth muscle actin was suppressed indicating HSCs inactivation. Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31. We concluded that DFE or DPE could protect liver via different mechanisms. The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

No MeSH data available.


Related in: MedlinePlus

(a) Effect of date flesh extract (DFE), date pits extract (DPE), coffee and the combination groups on hydroxyproline content in hepatic tissue of CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (b) Light microscopic photomicrographs of liver tissue stained with Masson's trichrome stain (scale bar = 50 μm). (A) Control liver showing normal hepatic fibrous tissue distribution restricted mainly to the portal area, while demarcation between classic hepatic lobule is observed due to very delicate fibrous tissue. (B) Represent liver section of rat receiving CCl4 showing marked increase of fibrous tissue arranged in irregular way between degenerated cells and sinusoids, causing destruction of classic architecture of hepatic lobules. Liver sections from rats treated with coffee (C), DFE (D), DPE (E), and the combination of coffee + DFE (F) and coffee + DPE (G) showing marked decrease of abnormally extra deposited fibrous tissue. The improvement is prominent in DFE than coffee alone or DPE alone. Sections from rats receiving combination showed apparently normal amount and distribution of fibrous tissue. (c) Effect of date flesh extract (DFE), date pits extract (DPE), coffee, and the combination groups on hepatic levels of transforming growth factor beta-1 (TGF-β1) in CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group; c: significantly different from coffee-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (d) Light microscopic photomicrographs of liver tissue immunostained with primary anti-TGF-β1 antibody (scale bar = 50 μm). (A) Control liver showing normal very weak immune reactivity of hepatocytes cytoplasm while the nuclei are not stained, and also the endothelial cells of both central vein and hepatic sinusoids are not stained. (B) represents liver section of rat receiving CCl4 showing strong abnormal immune reactivity of most of hepatocytes' cytoplasm and nuclei, and also most of cells of structures of portal area show strong nuclear immune reactivity. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing few hepatocytes with strong ((C), (E)) or moderate (D) immune reactivity especially those around portal area. In (F) and (G) hepatocytes' cytoplasm and few cells of structures of portal areas show weak positivity especially in rats receiving a combination of coffee + DFE (F). (e) Light microscopic photomicrographs of liver tissue immunostained with primary anti-α-SMA antibody (scale bar = 50 μm). (A) Control liver showing normal positive immune reactivity of smooth muscle of the blood vessels of the portal area without immune staining positivity in between hepatocytes, while (B) represents liver section of rat receiving CCl4 in which strong abnormal distributed immune reactivity, especially around degenerated hepatocytes, is prominent. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing marked decrease of the immune reactivity outside portal areas especially in groups receiving DFE and the combination.
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fig6: (a) Effect of date flesh extract (DFE), date pits extract (DPE), coffee and the combination groups on hydroxyproline content in hepatic tissue of CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (b) Light microscopic photomicrographs of liver tissue stained with Masson's trichrome stain (scale bar = 50 μm). (A) Control liver showing normal hepatic fibrous tissue distribution restricted mainly to the portal area, while demarcation between classic hepatic lobule is observed due to very delicate fibrous tissue. (B) Represent liver section of rat receiving CCl4 showing marked increase of fibrous tissue arranged in irregular way between degenerated cells and sinusoids, causing destruction of classic architecture of hepatic lobules. Liver sections from rats treated with coffee (C), DFE (D), DPE (E), and the combination of coffee + DFE (F) and coffee + DPE (G) showing marked decrease of abnormally extra deposited fibrous tissue. The improvement is prominent in DFE than coffee alone or DPE alone. Sections from rats receiving combination showed apparently normal amount and distribution of fibrous tissue. (c) Effect of date flesh extract (DFE), date pits extract (DPE), coffee, and the combination groups on hepatic levels of transforming growth factor beta-1 (TGF-β1) in CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group; c: significantly different from coffee-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (d) Light microscopic photomicrographs of liver tissue immunostained with primary anti-TGF-β1 antibody (scale bar = 50 μm). (A) Control liver showing normal very weak immune reactivity of hepatocytes cytoplasm while the nuclei are not stained, and also the endothelial cells of both central vein and hepatic sinusoids are not stained. (B) represents liver section of rat receiving CCl4 showing strong abnormal immune reactivity of most of hepatocytes' cytoplasm and nuclei, and also most of cells of structures of portal area show strong nuclear immune reactivity. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing few hepatocytes with strong ((C), (E)) or moderate (D) immune reactivity especially those around portal area. In (F) and (G) hepatocytes' cytoplasm and few cells of structures of portal areas show weak positivity especially in rats receiving a combination of coffee + DFE (F). (e) Light microscopic photomicrographs of liver tissue immunostained with primary anti-α-SMA antibody (scale bar = 50 μm). (A) Control liver showing normal positive immune reactivity of smooth muscle of the blood vessels of the portal area without immune staining positivity in between hepatocytes, while (B) represents liver section of rat receiving CCl4 in which strong abnormal distributed immune reactivity, especially around degenerated hepatocytes, is prominent. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing marked decrease of the immune reactivity outside portal areas especially in groups receiving DFE and the combination.

Mentions: CCl4-intoxicated rats expressed significantly higher hepatic levels of proinflammatory cytokines (P < 0.001) including TNF-α, IL-1β, and IL-6, which have been shown to play important roles in the development of the fibrosis. However, remarkable decreases in the levels of all those three parameters were observed by the simultaneous administration of DFE and the combination of coffee + DFE and coffee + DPE (P < 0.001) and by DPE and coffee (P < 0.01) compared to CCl4-intoxicated rats. It was noted that DFE alone and the combination of coffee + DFE and coffee + DPE significantly improved the hepatic levels of TNF-α and IL-1β levels compared to coffee alone (Figures 5(a) and 5(c)); however, no significant differences were observed in the case of IL-6 (Figure 5(b)). In addition, the levels of TNF-α and IL-1β were significantly lowered by DFE alone compared to DPE alone (P < 0.001 and P < 0.01, resp.).


Aqueous Date Flesh or Pits Extract Attenuates Liver Fibrosis via Suppression of Hepatic Stellate Cell Activation and Reduction of Inflammatory Cytokines, Transforming Growth Factor- β 1 and Angiogenic Markers in Carbon Tetrachloride-Intoxicated Rats.

Al-Rasheed NM, Attia HA, Mohamad RA, Al-Rasheed NM, Al-Amin MA, Al-Onazi A - Evid Based Complement Alternat Med (2015)

(a) Effect of date flesh extract (DFE), date pits extract (DPE), coffee and the combination groups on hydroxyproline content in hepatic tissue of CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (b) Light microscopic photomicrographs of liver tissue stained with Masson's trichrome stain (scale bar = 50 μm). (A) Control liver showing normal hepatic fibrous tissue distribution restricted mainly to the portal area, while demarcation between classic hepatic lobule is observed due to very delicate fibrous tissue. (B) Represent liver section of rat receiving CCl4 showing marked increase of fibrous tissue arranged in irregular way between degenerated cells and sinusoids, causing destruction of classic architecture of hepatic lobules. Liver sections from rats treated with coffee (C), DFE (D), DPE (E), and the combination of coffee + DFE (F) and coffee + DPE (G) showing marked decrease of abnormally extra deposited fibrous tissue. The improvement is prominent in DFE than coffee alone or DPE alone. Sections from rats receiving combination showed apparently normal amount and distribution of fibrous tissue. (c) Effect of date flesh extract (DFE), date pits extract (DPE), coffee, and the combination groups on hepatic levels of transforming growth factor beta-1 (TGF-β1) in CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group; c: significantly different from coffee-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (d) Light microscopic photomicrographs of liver tissue immunostained with primary anti-TGF-β1 antibody (scale bar = 50 μm). (A) Control liver showing normal very weak immune reactivity of hepatocytes cytoplasm while the nuclei are not stained, and also the endothelial cells of both central vein and hepatic sinusoids are not stained. (B) represents liver section of rat receiving CCl4 showing strong abnormal immune reactivity of most of hepatocytes' cytoplasm and nuclei, and also most of cells of structures of portal area show strong nuclear immune reactivity. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing few hepatocytes with strong ((C), (E)) or moderate (D) immune reactivity especially those around portal area. In (F) and (G) hepatocytes' cytoplasm and few cells of structures of portal areas show weak positivity especially in rats receiving a combination of coffee + DFE (F). (e) Light microscopic photomicrographs of liver tissue immunostained with primary anti-α-SMA antibody (scale bar = 50 μm). (A) Control liver showing normal positive immune reactivity of smooth muscle of the blood vessels of the portal area without immune staining positivity in between hepatocytes, while (B) represents liver section of rat receiving CCl4 in which strong abnormal distributed immune reactivity, especially around degenerated hepatocytes, is prominent. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing marked decrease of the immune reactivity outside portal areas especially in groups receiving DFE and the combination.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: (a) Effect of date flesh extract (DFE), date pits extract (DPE), coffee and the combination groups on hydroxyproline content in hepatic tissue of CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (b) Light microscopic photomicrographs of liver tissue stained with Masson's trichrome stain (scale bar = 50 μm). (A) Control liver showing normal hepatic fibrous tissue distribution restricted mainly to the portal area, while demarcation between classic hepatic lobule is observed due to very delicate fibrous tissue. (B) Represent liver section of rat receiving CCl4 showing marked increase of fibrous tissue arranged in irregular way between degenerated cells and sinusoids, causing destruction of classic architecture of hepatic lobules. Liver sections from rats treated with coffee (C), DFE (D), DPE (E), and the combination of coffee + DFE (F) and coffee + DPE (G) showing marked decrease of abnormally extra deposited fibrous tissue. The improvement is prominent in DFE than coffee alone or DPE alone. Sections from rats receiving combination showed apparently normal amount and distribution of fibrous tissue. (c) Effect of date flesh extract (DFE), date pits extract (DPE), coffee, and the combination groups on hepatic levels of transforming growth factor beta-1 (TGF-β1) in CCl4-intoxicated rats. Values are expressed as mean ± SEM. a: significantly different from normal control group; b: significantly different from CCl4-treated group; c: significantly different from coffee-treated group. ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. (d) Light microscopic photomicrographs of liver tissue immunostained with primary anti-TGF-β1 antibody (scale bar = 50 μm). (A) Control liver showing normal very weak immune reactivity of hepatocytes cytoplasm while the nuclei are not stained, and also the endothelial cells of both central vein and hepatic sinusoids are not stained. (B) represents liver section of rat receiving CCl4 showing strong abnormal immune reactivity of most of hepatocytes' cytoplasm and nuclei, and also most of cells of structures of portal area show strong nuclear immune reactivity. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing few hepatocytes with strong ((C), (E)) or moderate (D) immune reactivity especially those around portal area. In (F) and (G) hepatocytes' cytoplasm and few cells of structures of portal areas show weak positivity especially in rats receiving a combination of coffee + DFE (F). (e) Light microscopic photomicrographs of liver tissue immunostained with primary anti-α-SMA antibody (scale bar = 50 μm). (A) Control liver showing normal positive immune reactivity of smooth muscle of the blood vessels of the portal area without immune staining positivity in between hepatocytes, while (B) represents liver section of rat receiving CCl4 in which strong abnormal distributed immune reactivity, especially around degenerated hepatocytes, is prominent. Panels (C), (D), (E), (F), and (G) represent liver sections from rat receiving coffee, DFE, DPE, coffee + DFE, and coffee + DPE, respectively, showing marked decrease of the immune reactivity outside portal areas especially in groups receiving DFE and the combination.
Mentions: CCl4-intoxicated rats expressed significantly higher hepatic levels of proinflammatory cytokines (P < 0.001) including TNF-α, IL-1β, and IL-6, which have been shown to play important roles in the development of the fibrosis. However, remarkable decreases in the levels of all those three parameters were observed by the simultaneous administration of DFE and the combination of coffee + DFE and coffee + DPE (P < 0.001) and by DPE and coffee (P < 0.01) compared to CCl4-intoxicated rats. It was noted that DFE alone and the combination of coffee + DFE and coffee + DPE significantly improved the hepatic levels of TNF-α and IL-1β levels compared to coffee alone (Figures 5(a) and 5(c)); however, no significant differences were observed in the case of IL-6 (Figure 5(b)). In addition, the levels of TNF-α and IL-1β were significantly lowered by DFE alone compared to DPE alone (P < 0.001 and P < 0.01, resp.).

Bottom Line: Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31.We concluded that DFE or DPE could protect liver via different mechanisms.The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia.

ABSTRACT
Previous data indicated the protective effect of date fruit extract on oxidative damage in rat liver. However, the hepatoprotective effects via other mechanisms have not been investigated. This study was performed to evaluate the antifibrotic effect of date flesh extract (DFE) or date pits extract (DPE) via inactivation of hepatic stellate cells (HSCs), reducing the levels of inflammatory, fibrotic and angiogenic markers. Coffee was used as reference hepatoprotective agent. Liver fibrosis was induced by injection of CCl4 (0.4 mL/kg) three times weekly for 8 weeks. DFE, DPE (6 mL/kg), coffee (300 mg/kg), and combination of coffee + DFE and coffee + DPE were given to CCl4-intoxicated rats daily for 8 weeks. DFE, DPE, and their combination with coffee attenuated the elevated levels of inflammatory cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-1β. The increased levels of transforming growth factor-β1 and collagen deposition in injured liver were alleviated by both extracts. CCl4-induced expression of α-smooth muscle actin was suppressed indicating HSCs inactivation. Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31. We concluded that DFE or DPE could protect liver via different mechanisms. The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

No MeSH data available.


Related in: MedlinePlus