Combined versus single locoregional therapy in the treatment of unresectable hepatocellular carcinoma

AbstractIntroductionSurgical and locoregional therapies are different options in HCC treatment, several locoregional techniques are used.PurposeThis study aimed to assess the effectiveness of transarterial chemoembolization (TACE), radiofrequency ablation (RFA) and combined therapy, in HCC management.Materials and methodsThe study was conducted at our University Hospital, from August 2011 to February 2013. It included 60 patients with HCC (40 males and 20 females, age ranged between 45 and 70years). Patients were classified into 3 groups, group 1 treated with TACE, group 2 with RFA, and group 3 with both techniques. Response was assessed by triphasic CT and alpha fetoprotein. Patients were classified into good and poor responders after one and six months and one year. Patients’ survival and incidence of recurrence were recorded.ResultsThe percentage of good responders was greater with combined therapy than with TACE and RFA (90%, 70%, and 60% respectively). The overall survival was 75% and the recurrence free survival was 60% in TACE, 90%, and 45% in RFA and 95% and 90% in combined therapy respectively.ConclusionCombined therapy is superior regarding good response, overall survival, and free recurrence survival than either TACE or RFA alone

Exosomal miR-940 maintains SRC-mediated oncogenic activity in cancer cells: a possible role for exosomal disposal of tumor suppressor miRNAs

Exosomes have emerged as important mediators of diverse biological functions including tumor suppression, tumor progression, invasion, immune escape and cell-to-cell communication, through the release of molecules such as mRNAs, miRNAs, and proteins. Here, we identified differentially expressed exosomal miRNAs between normal epithelial ovarian cell line and both resistant and sensitive ovarian cancer (OC) cell lines. We found miR-940 as abundant in exosomes from SKOV3-IP1, HeyA8, and HeyA8-MDR cells. The high expression of miR-940 is associated with better survival in patients with ovarian serous cystadenocarcinoma. Ectopic expression of miR-940 inhibited proliferation, colony formation, invasion, and migration and triggered G0/G1 cell cycle arrest and apoptosis in OC cells. Overexpression of miR-940 also inhibited tumor cell growth in vivo. We showed that proto-oncogene tyrosine-protein kinase (SRC) is directly targeted by miR-940 and that miR-940 inhibited SRC expression at mRNA and protein levels. Following this inhibition, the expression of proteins downstream of SRC, such as FAK, paxillin and Akt was also reduced. Collectively, our results suggest that OC cells secrete the tumor-suppressive miR-940 into the extracellular environment via exosomes, to maintain their invasiveness and tumorigenic phenotype

Prophylactic role of β-carotene against acrylonitrile-induced testicular toxicity in rats: Physiological and microscopical studies

Acrylonitrile (ACN) is an aliphatic nitrile product which is extensively used in various synthetic chemical industries. ACN is known to exert toxic actions to human beings as well as experimental animals. The present study was designed to examine the ability of β-carotene, a naturally occurring antioxidant, to attenuate ACN-induced testicular toxicity in adult albino rats. Daily oral administration of ACN at a dose level of 30 mg/kg b.w. (7.2 mg/animal) to male rats for a period of 5 days significantly reduced the levels of serum testosterone (T), androsterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which indicate injury to the testis function. Also, it decreased serum and testicular glutathione (GSH) content and glutathione-S-transferase (GST) activity. While, ACN induced lipid peroxidation as indicated by markedly increased malondialdehyde (MDA). ACN intoxication also induced marked alterations in most of the seminiferous tubules including germ cell depletion, tubular atrophy, maturation arrest, complete necrosis as well as multinucleated giant cell formation. Expansion of intertubular spaces and interstitial haemorrhage were also illustrated. Ultrastructural examination of the seminiferous tubules revealed thickened boundary tissue, pyknosis of Sertoli cell nuclei, damaged mitochondria and smooth endoplasmic reticulum-derived vacuoles. Spermatogenic cells also demonstrated altered cytoplasmic organelles, vacuoles of varying sizes and deformed spermatids. Mitochondrial disruption and a decrease in the amount of smooth endoplasmic reticulum were observed in Leydig cells. Compared to ACN-treated animals, pretreatment with β-carotene and its co-administration with ACN once daily at a dose of 40 mg/kg b.w. (9.6 mg/animal) for 30 days induced a remarkable degree of improvement in the levels of endocrine parameters including T, androsterone, FSH and LH. Also, it mitigates serum and testicular GSH content, GST activity and MDA level. Moreover, it protects testicular tissues and cell structures. In conclusion, the present results clearly demonstrate the prophylactic role of β-carotene against ACN-induced testicular toxicity in rats

Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways.

Mangiferin (MF), a xanthonoid from Mangifera indica, has been proved to have antisecretory and antioxidant gastroprotective effects against different gastric ulcer models; however, its molecular mechanism has not been previously elucidated. Therefore, the aim of this study was to test its modulatory effect on several signaling pathways using the ischemia/reperfusion model for the first time. Animals were treated with MF, omeprazole (OMP), and the vehicle. The mechanistic studies revealed that MF mediated its gastroprotective effect partly via inducing the expression of Nrf2, HO-1 and PPAR-γ along with downregulating that of NF-κB. Surprisingly, the effect of MF, especially the high dose, exceeded that mediated by OMP except for Nrf2. The molecular results were reflected on the biomarkers measured, where the antioxidant effect of MF was manifested by increasing total antioxidant capacity and glutathione, besides normalizing malondialdehyde level. Additionally, MF decreased the I/R-induced nitric oxide elevation, an effect that was better than that of OMP. In the serum, MF, dose dependently, enhanced endothelial nitric oxide synthase, while reduced the inducible isoform. Regarding the anti-inflammatory effect of MF, it reduced serum level of IL-1β and sE-selectin, effects that were mirrored on the tissue level of myeloperoxidase, the neutrophil infiltration marker. In addition, MF possessed an antiapoptotic character evidenced by elevating Bcl-2 level and reducing that of caspase-3 in a dose related order. As a conclusion, the intimated gastroprotective mechanisms of MF are mediated, partially, by modulation of oxidative stress, inflammation and apoptosis possibly via the Nrf2/HO-1, PPAR-γ/NF-κB signaling pathways

In Vivo Investigation of the Ameliorating Effect of Tempol against MIA-Induced Knee Osteoarthritis in Rats: Involvement of TGF-β1/SMAD3/NOX4 Cue

Osteoarthritis (OA) is a complex disease characterized by structural, functional, and metabolic deteriorations of the whole joint and periarticular tissues. In the current study, we aimed to investigate the possible effects of tempol on knee OA induced by the chemical chondrotoxic monosodium iodoacetate (MIA) which closely mimics both the pain and structural changes associated with human OA. Rats were administrated oral tempol (100 mg/kg) one week post-MIA injection (3 mg/50 μL saline) at the right knee joints for 21 consecutive days. Tempol improved motor performance and debilitated the MIA-related radiological and histological alterations. Moreover, it subsided the knee joint swelling. Tempol decreased the cartilage degradation-related biomarkers as matrix metalloproteinase-13, bone alkaline phosphatase (bone ALP), and fibulin-3. The superoxide dismutase mimetic effect of tempol was accompanied by decreased NADPH oxidase 4 (NOX4), inflammatory mediators, nuclear factor-kappa B (NF-κB), over-released transforming growth factor-β1 (TGF-β1). Tempol decreased the expression of chemokine (C-C motif) ligand 2 (CCL2). On the molecular level, tempol reduced the phosphorylated protein levels of p38 mitogen-activated protein kinase (MAPK), and small mother against decapentaplegic 3 homologs (SMAD3). These findings suggest the promising role of tempol in ameliorating MIA-induced knee OA in rats via collateral suppression of the catabolic signaling cascades including TGF-β1/SMAD3/NOX4, and NOX4/p38MAPK/NF-κB and therefore modulation of oxidative stress, catabolic inflammatory cascades, chondrocyte metabolic homeostasis

In Vivo Investigation of the Ameliorating Effect of Tempol against MIA-Induced Knee Osteoarthritis in Rats: Involvement of TGF-β1/SMAD3/NOX4 Cue

Osteoarthritis (OA) is a complex disease characterized by structural, functional, and metabolic deteriorations of the whole joint and periarticular tissues. In the current study, we aimed to investigate the possible effects of tempol on knee OA induced by the chemical chondrotoxic monosodium iodoacetate (MIA) which closely mimics both the pain and structural changes associated with human OA. Rats were administrated oral tempol (100 mg/kg) one week post-MIA injection (3 mg/50 μL saline) at the right knee joints for 21 consecutive days. Tempol improved motor performance and debilitated the MIA-related radiological and histological alterations. Moreover, it subsided the knee joint swelling. Tempol decreased the cartilage degradation-related biomarkers as matrix metalloproteinase-13, bone alkaline phosphatase (bone ALP), and fibulin-3. The superoxide dismutase mimetic effect of tempol was accompanied by decreased NADPH oxidase 4 (NOX4), inflammatory mediators, nuclear factor-kappa B (NF-κB), over-released transforming growth factor-β1 (TGF-β1). Tempol decreased the expression of chemokine (C-C motif) ligand 2 (CCL2). On the molecular level, tempol reduced the phosphorylated protein levels of p38 mitogen-activated protein kinase (MAPK), and small mother against decapentaplegic 3 homologs (SMAD3). These findings suggest the promising role of tempol in ameliorating MIA-induced knee OA in rats via collateral suppression of the catabolic signaling cascades including TGF-β1/SMAD3/NOX4, and NOX4/p38MAPK/NF-κB and therefore modulation of oxidative stress, catabolic inflammatory cascades, chondrocyte metabolic homeostasis

Effect of mangiferin and omeprazole on the mRNA expression of (A) Nrf2, (B) HO-1, (C) PPAR-γ, and (D) NF-κB genes in ischemia/reperfused rats.

<p>Mangiferin (10 & 20 mg/kg; MF₁₀ & MF₂₀) and omeprazole (20 mg/kg; OMP₂₀) were administered intraperitoneally 30 min before induction of ischemia/reperfusion (I/R) and for 3 days after reperfusion. Values are means of 7–9 rats ± S.E.M; as compared with sham (*), I/R (^@), MF₁₀ (δ), and OMP (#) treated groups (one-way ANOVA followed by Student-Newman-Keuls multiple comparison tests) at <i>P</i>< 0.05.</p

Representative photomicrographs of stomach mucosa.

<p>[A] Sham-operated rat section shows normal gastric mucosal (mu), submucosal (sm) and muscularis (mL) architecture. [B] Ischemia/reperfusion (I/R) sections show sloughed mucosa (m), juxtraposed with underlying haemorrhage (black arrow), [C] severe vascular congestion (V), focal inflammatory cells infiltration (m) and oedema (O) in submucosa. [D] MF₁₀ section reveals only congestion in the submucosal blood vessels (V) with mild inflammatory cell infiltration (yellow arrow) and/or edema. [E] MF₂₀ section, similar to sham-operated control, shows normal intact histological structure except for very mild vascular congestion (v) in the submucosa. [F] OMP₂₀ section mimics that of MF₂₀, but shows only congested blood vessels (V) in the submucosal layer.</p

Effect of mangiferin and omeprazole on ulcer index in ischemia/reperfused rats.

<p>Mangiferin (10 & 20 mg/kg; MF₁₀ & MF₂₀) and omeprazole (20 mg/kg; OMP₂₀) were administered intraperitoneally 30 min. before induction of ischemia/ reperfusion (I/R) and for 3 days after reperfusion. Values are means of 7–9 rats ± S.E.M; as compared with sham (*), I/R (^@), MF₁₀ (δ), and OMP (#) treated groups (one-way ANOVA followed by Student-Newman-Keuls multiple comparison tests), <i>P</i>< 0.05.</p