The fibrolytic potentials of vitamin D and thymoquinone remedial therapies: insights from liver fibrosis established by CCl4 in rats

Abstract

BackgroundVitamin D (VitD) and thymoquinone (TQ) are nutraceutical agents with well-known immunomodulatory and hepatoprotective properties. This study measured whether VitD and TQ, individually or combined, could have direct fibrolytic activities and/or enhanced performance during remedial treatment of liver fibrosis established by CCl4 in rats.MethodsEighty five male Wistar rats were used as 10 negative controls (NC) and the remainders were distributed equally into 5 groups: short (S-PC) and long (L-PC) positive controls, TQ, VitD and VitD/TQ groups. CCl4 was injected for 7 weeks followed by a week of no intervention. TQ and/or VitD were given orally (3 days/week) from week 9 and euthanasia was at week 17 for all groups except the S-PC was at week 9. Following histopathological and digital image analyses, TGF-β1, IL-6, IL-10, IL-22 and MMP-9 were measured by ELISA in liver homogenates while the corresponding cytokine receptors were measured by immunohistochemistry. The mRNA expressions of all molecules were measured by quantitative RT-PCR.ResultsFibrosis was evident in both PC-groups and was significantly more advanced in the L-PC than S-PC, reaching to cirrhosis. The concentrations of TGF-β1, IL-6, IL-22 and their receptors were significantly higher (P < 0.05) simultaneously with significantly lower (P < 0.05) concentrations of MMP-9, IL-10 and IL-10 receptors in the S-PC and L-PC than the NC-group. TQ and VitD monotherapies showed significantly less fibrosis than L-PC but were similar to S-PC. Both remedial monotherapies also resulted in significant decreases of TGF-β1, IL-6, IL-22 and their receptors together with significant increases of MMP-9 and IL-10 system compared with S-PC and L-PC groups. Interestingly, dual therapy resulted in the most significant improvement in fibrosis score and index, yet was significantly higher (P < 0.05) than the NC-group, and concurred with the utmost significant restorations of all candidate genes and proteins.ConclusionsVitD and TQ exhibited comparable anti-fibrogenic effects and modulated several pro- and anti-fibrotic mediators. Additionally, VitD/TQ dual therapy alleviated the previously established liver fibrosis simultaneously with significantly enhanced actions at the molecular level. More studies are required to explorer the therapeutic value of TQ and VitD against liver fibrosis in human.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1040-4) contains supplementary material, which is available to authorized users.

Vitamin D3 and calcium cosupplementation alleviates cadmium hepatotoxicity in the rat: Enhanced antioxidative and anti‐inflammatory actions by remodeling cellular calcium pathways

“…A final hydroxylation occurs by renal tubular Cyp27b1 enzyme to form active VD (VD 3 ) . VD 3 initiates its cellular actions by activating its nuclear receptor (vitamin D receptor [VDR]), which is abundantly expressed in hepatic tissues . The bioavailability of active VD 3 is generally regulated in the targeted organs, including the liver, by the Cyp24a1 catalyzing enzyme …”

“…[19,20] Vitamin D (VD) is a plethoric steroid hormone associated with potent antioxidative and anti-inflammatory actions alongside its well-established calcaemic effects. [21,22] The main systemic form of VD, 25-hydroxy vitamin D (25-OH VD), is synthesized by the hepatic microsomal Cyp2R1 and mitochondrial Cyp27a1 hydroxylases. [21,22] Circulatory 25-OH VD is transported reversibly attached to its specific vitamin D-binding protein (VDBP), which is also mainly produced by the liver.…”

“…[21,22] The main systemic form of VD, 25-hydroxy vitamin D (25-OH VD), is synthesized by the hepatic microsomal Cyp2R1 and mitochondrial Cyp27a1 hydroxylases. [21,22] Circulatory 25-OH VD is transported reversibly attached to its specific vitamin D-binding protein (VDBP), which is also mainly produced by the liver. [23,24] A final hydroxylation occurs by renal tubular Cyp27b1 enzyme to form active VD (VD 3 ).…”

“…[23,24] VD 3 initiates its cellular actions by activating its nuclear receptor (vitamin D receptor [VDR]), which is abundantly expressed in hepatic tissues. [21,22] The bioavailability of active VD 3 is generally regulated in the targeted organs, including the liver, by the Cyp24a1 catalyzing enzyme. [21,22] Many reports have shown major declines in systemic VD with chronic Cd toxicity.…”

“…[21,22] The bioavailability of active VD 3 is generally regulated in the targeted organs, including the liver, by the Cyp24a1 catalyzing enzyme. [21,22] Many reports have shown major declines in systemic VD with chronic Cd toxicity. [25][26][27] Moreover, the intestinal absorption of Cd and its toxic effects were enhanced in animals fed with VD 3 or Ca 2+deficient diets.…”