Basma G. Eid

Icariin protects against thioacetamide-induced liver fibrosis in rats: Implication of anti-angiogenic and anti-autophagic properties

BACKGROUND Liver fibrosis is a major health problem. The current study evaluated the potential of icariin (ICA) to guard against thioacetamide (TAA)-induced liver fibrosis in rats. METHODS Four groups of male rats were treated as follows: group 1 was the control group, group 2 was given TAA (200mg/kg), group 3 was administered ICA (50mg/kg) and TAA (200mg/kg), and group 4 was given ICA (50mg/kg) alone. Animal treatment was continued for four weeks. RESULTS Co-administration of ICA guarded against TAA hepatotoxicity as indicated by significant inhibition in the rise of serum ALT and AST activities and albumin concentrations. This was accompanied by inhibition of reduced glutathione depletion, superoxide dismutase exhaustion, and lipid peroxide accumulation. In addition, ICA inhibited the pathological alterations in liver architecture induced by TAA. The antifibrotic activity of ICA was verified by reduced hepatic collagen deposition in liver sections stained with Massons trichrome and hepatic Col-1α mRNA and hydroxyproline contents compared to the TAA-treated group. The antiangiogenic activity of ICA was evidenced by lowered levels of mRNA of Ang-1 and protein expression of VEGF, PDGF-β, and CTGF immunohistochemically. Further, the anti-autophagic property of ICA was evidenced by amelioration of the decrease in mTOR and p70S6 kinase expression and an increase in TLR4, NFκB, IL1-β, and COX-2 immunohistochemically. Moreover, ICA antagonized the increase in HMGB1, TGF-β, and Beclin-1 and the decrease in BAMBI hepatic mRNA levels. CONCLUSIONS ICA inhibits TAA-induced liver fibrosis in rats, possibly via inhibition of angiogenesis and autophagy.

Proanthocyanidin protects against cisplatin‐induced oxidative liver damage through inhibition of inflammation and NF‐κβ/TLR‐4 pathway

Although cisplatin (CIS) is a highly effective anticancer drug, hepatotoxicity is one of the most common adverse effects associated with its use. Recently, reactive oxygen species (ROS) and inflammation are suggested to be key factors in the pathophysiology of CIS‐induced acute liver damage. The aim of this study is to investigate the possible protective effect of proanthocyanidin (PRO) against CIS‐induced acute hepatotoxicity. Rats were divided into four groups: 1, Control; 2, PRO; 3, CIS; and 4, PRO + CIS. Biochemical studies and histopathology were used to assess liver damage. ROS, inflammatory cytokines, nuclear factor kappa beta (NF‐κβ), inducible cyclooxygenase enzyme (COX‐2), inducible nitric oxide synthase (iNOS), toll‐like receptor‐4 (TLR‐4) gene expression, and apoptotic markers were also assessed. PRO pretreatment protected the liver against CIS‐induced toxicity as indicated by decreased plasma levels of liver function enzymes and the normal liver histopathology observed in the PRO + CIS group. PRO pretreatment also diminished indicators of oxidative stress in the liver, including nitric oxide (NO) and malondialdehyde (MDA). It also increased the antioxidants, reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) in the liver. Plasma interleukin‐1 beta (IL‐1β), IL‐6, and tumor necrosis factor‐alpha (TNF‐α) were all reduced. Liver gene expression of NF‐κβ, COX‐2, iNOS, and TLR‐4 were all downregulated. Furthermore, PRO administration downregulated the liver expression of the apoptotic marker, Bax, while upregulated the antiapoptotic marker, Bcl2. In conclusion, our results revealed that PRO may protect against CIS‐induced acute liver damage mainly through inhibition of ROS, inflammation, and apoptosis.

The vasodilatory effect of allopurinol mediates its antihypertensive effect: Effects on calcium movement and cardiac hemodynamics

Despite the reported reduction in blood pressure in hypertensive patients treated with allopurinol, the mechanism of the allopurinol hypotensive effect is still unclear. In the current study, the hypotensive effect of allopurinol has been fully investigated in hypertensive rats. Hypertension was induced in rats by angiotensin II (120 ng/min/kg) infusion for two weeks. Rats were then subjected to real-time recording of blood pressure, left ventricular pressure and volume and surface ECG. After 10 min of basal recording, allopurinol was slowly injected into the femoral vein with a dose of 10 μmole/kg. Then, invasive blood pressure, cardiac hemodynamics and ECG were continuously recorded for an additional 20 min. In addition, the vasodilation effect of allopurinol was studied using the isolated artery technique. Allopurinol injection reduced systolic, diastolic and pulse blood pressure. Allopurinol suppressed both cardiac systolic and diastolic hemodynamics as is apparent from the reduction in the rate of rise and the rate of fall in left ventricular pressure. Allopurinol reduced the general cardiac output quickly. Allopurinol addition to the organ bath (10-1000 μM) produced significant vasodilation of PE pre-constricted aortae that was not affected by endothelium denudation, L-NAME or indomethacin. However, allopurinol ameliorated the calcium induced contraction of aorta pre-constricted with KCl in calcium-free media. Erk or ROCK inhibition did not attenuated allopurinol produced vasodilation. In conclusion, allopurinol has an antihypertensive effect that is mediated, probably, by reducing cardiac output and decreasing vascular resistance. The vasodilator effect of allopurinol is most likely mediated by calcium blocking activities.

Anticonvulsant and Neuroprotective Activities of Phragmanthera austroarabica Extract in Pentylenetetrazole-Kindled Mice

Anticonvulsant and neuroprotective activity of Phragmanthera austroarabica extract were tested in pentylenetetrazole-kindled mice. All the chemical constituents of the plant extract were identified. Additionally, the extract was standardized and proved to contain total phenolic contents equal to 379.92 ± 1.32 mg gallic acid equivalents/g dry plant extract. Induction of kindling was achieved by repeated intraperitoneal administration of pentylenetetrazole (35 mg/kg) twice weekly. Male albino mice were given P. austroarabica extract (200, 400, or 800 mg/kg). The two higher doses (400 or 800 mg/kg) of the extract significantly caused notable reduction in seizure activity and hippocampal malondialdehyde level compared to pentylenetetrazole control group. The highest dose enhanced cortical GSH level and showed intact DNA in the laddering assay. Upon studying the neuroprotective effect, mice treated with the higher dose of the extract demonstrated an improvement in the percent of surviving neurons in the cortex and hippocampus. We concluded that P. austroarabica extract ameliorated seizure activity and protected cortical and hippocampal neurons against pentylenetetrazole-induced kindling in mice.

Rutin Isolated from Chrozophora tinctoria Enhances Bone Cell Proliferation and Ossification Markers

Osteoporosis is a chronic disease in which the skeleton loses a weighty proportion of its mineralized mass and mechanical pliability. Currently available antiosteoporotic agents suffer adverse effects that include elevated risk of thrombosis and cancer. Phytochemicals may constitute a safer and effective option. In the current work, six flavonoids were obtained from Chrozophora tinctoria and identified as amentoflavone (1), apigenin-7-O-β-d-glucopyranoside (2), apigenin-7-O-6′′-E-p-coumaroyl-β-d-glucopyranoside (3), acacetin-7-O-β-d-[α-l-rhamnosyl(1→6)]3′′-E-p-coumaroyl glucopyranoside (4), apigenin-7-O-(6′′-Z-p-coumaroyl)-β-d-glucopyranoside (5), and rutin (6). An extensive review of the literature as well as NMR and mass spectral techniques was employed in order to elucidate the compound structures. Proliferation was enhanced in MCF7, MG-63, and SAOS-2 cells after exposure to subcytotoxic levels of the tested flavonoids. Rutin was chosen for subsequent studies in SAOS-2 cells. Rutin was not found to cause any alteration in the index of proliferation of these cells, when examining the cell cycle distribution by DNA flowcytometric analysis. Rutin was, however, found to increase osteocyte and osteoblast-related gene expression and lower the expression of RUNX suppressor and osteoclast genes. When examining the influence of rutin on vitamin D levels and the activity of alkaline phosphatase enzyme, it was found to enhance both, while decreasing acid phosphatase which is a marker of osteoporosis. Thus, rutin enhances proliferation and ossification markers in bone cells.

2-Methoxyestradiol Attenuates Testosterone-Induced Benign Prostate Hyperplasia in Rats through Inhibition of HIF-1α/TGF-β/Smad2 Axis

Benign prostatic hyperplasia (BPH) is a common disorder in the male population. 2-Methoxyestradiol (2ME) is an end metabolite of estrogens with pleiotropic pharmacological properties. This study aimed to explore the potential ameliorative effects of 2ME against testosterone-induced BPH in rats. 2-Methoxyestradiol (50 and 100 mg/kg, dissolved in DMSO) prevented the rise in prostatic index and weight in comparison to testosterone-alone-treated animals for 2 weeks. Histological examination indicated that 2ME ameliorated pathological changes in prostate architecture. This was confirmed by the ability of 2ME to decrease the glandular epithelial height when compared to the testosterone group. Also, 2ME improved testosterone-induced oxidative stress as it inhibited the rise in lipid peroxide content and the exhaustion of superoxide dismutase (SOD) activity. The beneficial effects of 2ME against the development of BPH were substantiated by assessing proliferation markers, preventing the rise in cyclin D1 protein expression and enhancing Bax/Bcl2 mRNA ratio. It significantly reduced prostate content of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), nuclear factor κB (NF-κB), and transforming growth factor β (TGF-β). In addition, 2ME reduced hypoxia-inducible factor 1-α (HIF-1α) and phospho-Smad2 (p-Smad2) protein expression compared to the testosterone group. In conclusion, 2ME attenuates experimentally induced BPH by testosterone in rats through, at least partly, inhibition of HIF-1α/TGF-β/Smad2 axis.

Ginger Ingredients Alleviate Diabetic Prostatic Complications: Effect on Oxidative Stress and Fibrosis

Prostatic complications are common in patients with diabetes. This study investigated the effect of different ginger ingredients: zingerone, geraniol, and 6-gingerol on the prostate in diabetic rats. Diabetes was induced in Wistar rats by streptozotocin intraperitoneal injection (50 mg/kg), and the rats were left for 10 weeks to develop prostatic complications. In diabetic treated groups, rats received daily oral zingerone, geraniol, and 6-gingerol in doses of 20, 200, and 75 mg/kg, respectively, in the last 8 weeks. Treatment with the compounds caused changes in the ventral prostate of diabetic animals as indicated by the columnar ductal epithelium and dense secretions. There was an amelioration of oxidative stress as evidenced by the lowering of prostate malondialdehyde and elevating prostate oxidized to reduced glutathione (GSH/GSSG) ratios by geraniol and 6-gingerol. None of the three ginger ingredients affected the hyperglycemia, reduction in body weight gain, and testosterone deficiency seen in diabetic animals. Interleukin-1β and interleukin-6 levels remained unchanged. However, zingerone and geraniol ameliorated the fibrosis in diabetic prostate through suppressing the elevated prostate transforming growth factor beta 1 (TGFβ1) and collagen IV. Therefore, ginger ingredients could be beneficial in alleviating diabetic prostatic complications through suppressing oxidative stress and tissue fibrosis.