Siah2 inhibitor and the metabolic antagonist Oxamate retard colon cancer progression and downregulate PD1 expression.

BACKGROUND: Solid tumors such as colon cancer are characterized by rapid and sustained cell proliferation, which ultimately results in hypoxia, induction of hypoxia-inducible factor-1α (HIF-1α), and activation of glycolysis to promote tumor survival and immune evasion. We hypothesized that a combinatorial approach of menadione (MEN) as an indirect HIF-1α inhibitor and sodium oxamate (OX) as a glycolysis inhibitor may be a promising treatment strategy for colon cancer. OBJECTIVES: We investigated the potential efficacy of this combination for promoting an antitumor immune response and suppressing tumor growth in a rat model of colon cancer. METHODS: Colon cancer was induced by once-weekly subcutaneous injection of 20 mg/kg dimethylhydrazine (DMH) for 16 weeks. Control rats received the vehicle and then no further treatment (negative control) or MEN plus OX for 4 weeks (drug control). Dimethylhydrazine-treated rats were then randomly allocated to four groups: DMH alone group and other groups treated with MEN, OX, and a combination of (MEN and OX) for 4 weeks. Serum samples were assayed for the tumor marker carbohydrate antigen (CA19.9), while expression levels of HIF-1α, caspase-3, PHD3, LDH, and PD1 were evaluated in colon tissue samples by immunoassay and qRT-PCR. Additionally, Ki-67 and Siah2 expression levels were examined by immunohistochemistry. RESULTS: The combination of MEN plus OX demonstrated a greater inhibitory effect on the expression levels of HIF-1α, Siah2, LDH, Ki-67, and PD1, and greater enhancement of caspase-3 and PHD3 expression in colon cancer tissues than either drug alone. CONCLUSION: Simultaneous targeting of hypoxia and glycolysis pathways by a combination of MEN and OX could be a promising therapy for inhibiting colon cancer cell growth and promoting antitumor immunity [1].

Mechanical Behavior of Laminated Glass Polymer Interlayer Subjected to Environmental Effects.

It is known that weathering action has a significant impact on polymer interlayer materials, and previous studies have evaluated certain aspects of weathering such as temperature, humidity, and UV radiation. In this paper, the environmental effect on the mechanical properties of the virgin and cured/processed polymer interlayer materials will be studied. Three polymer interlayer materials were focused, i.e., Polyvinyl butyral (PVB), Ethylene-vinyl acetate (EVA), and Ionomer (SG), due to their industrial interest. Testing setups were designed to apply the environmental effects and perform mechanical testing on the polymeric materials. Four environmental effects were studied, including water submersion (E1), constant high temperature (E2), cyclic temperature with low relative humidity (E3), cyclic temperature, and relative humidity (E4). After the exposure of these materials to these environmental effects, the samples were prepared and mechanically tested. Uniaxial tests were performed under static and high strain rates (around 45-1). It was found that under dynamic load, the properties of EVA such as the strength, maximum strain, and the toughness were not significantly affected by the environmental effects. SG5000 properties were significantly affected.

Perindopril sensitizes hepatocellular carcinoma to chemotherapy: A possible role of leptin / Wnt/ ß-catenin axis with subsequent inhibition of liver cancer stem cells.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. The major challenge in managing HCC is the resistance to chemotherapy. Leptin hormone is associated with different oncogenic pathways implicated in drug resistance. Angiotensin II was found to decrease the production and secretion of leptin. Objective: This study investigated the potential role of an ACEI perindopril as a chemosensitizer agent to sorafenib. Method: HCC was induced in mice using a single dose of diethylnitrosamine DENA (200 mg/kg) followed by phenobarbital 0.05% in drinking water for 16 weeks. Mice were then treated with perindopril (1 mg/kg/day), Sorafenib (30 mg/kg/day), or both of them for another four weeks. Leptin, VEGF, MMP-9, Cyclin D1, EpCAM, and ß-catenin were measured using immunoassay while Wnt and ALDH1 were assayed using western blotting assay. Results: Perindopril whether alone or in combination with sorafenib decrease liver enzymes and preserve the liver architecture. Our study revealed that perindopril significantly increased the antineoplastic, antiangiogenic as well as anti-metastatic effects of sorafenib. This effect was correlated with the downregulation of the leptin / Wnt / ß-catenin pathway and overexpression of ALDH1 while downregulation of EpCAM. Conclusion: This study presents perindopril as a potential chemosensitizer agent that works through decreased expression of the leptin / Wnt / ß-catenin pathway.

Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells.

BACKGROUND: Hypoxic microenvironment of colon cancer is associated with HIF-1α upregulation. HIF-1α response elements are responsible for autophagy induction that promotes tumor proliferation. Moreover, HIF-1α induces tumor cell proliferation via maintaining cancer stem cells (CSCs) survival. Siah2 is E3 ubiquitin ligase that indirectly stabilizes HIF-1α. We hypothesized that dual inhibition of Siah2 as well as autophagy could be a promising approach that may inhibit CSCs growth. AIM OF THE WORK: This study investigated the possible effect of vitamin K3 as a Siah2 inhibitor and hydroxychloroquine as an autophagy inhibitor in colon cancer management. The effect (if any) of these agents on CSCs growth will be also manipulated. METHODS: Colon cancer was induced by dimethylhydrazine. MDA and GSH were selected as oxidative stress markers, Expression of HIF-1α, Caspase-3, VEGF, MMP-9, EpCAM, SCF, and CA19.9 were assayed using immunoassay. The Western blot technique was used to assess LC3Ⅰ, CD44, and CD133 whereas RT-PCR was used to investigate PHD3 and CD44 in colon tissues. Additionally, Ki-67 and Siah2 were detected immunohistochemically. RESULTS: vitamin K3 and hydroxychloroquine either alone or in combination downregulated the expression of Siah2 and HIF-1α through upregulating PHD3 in colon tissues. This combination significantly downregulated MDA, Ki-67, VEGF, and MMP-9 expression and upregulated the expression of GSH and caspase-3. LC3Ⅰ was also upregulated. Interestingly, these therapeutic options were correlated with down-regulation of the cancer stem cell marker such as CD44 and EpCAM. CONCLUSION: Our results suggested that suppression of both Siah2-PHD3-HIF-1α axis and autophagy retard colon cancer proliferation and dampened CSCs.

Structural Behavior of RC Beams Containing Unreinforced Drilled Openings with and without CFRP Strengthening.

Construction deficiencies can cause serious problems that significantly decrease the design strength of concrete structures, such as the unreinforced drilled openings. With the absence of sufficient reinforcement, the stress concentrations generated around the opening corners produce cracks in the beams. The size and location of the opening significantly affect the behavior of the beam under static and dynamic load. In this work, an experimental and numerical program was performed to investigate the behavior of drilled reinforced concrete beams with and without strengthening using CFRP sheets. Energy absorption and SDOF analyses were performed to preliminary assess the behavior of the beams under the dynamic load, such as blast. One control beam without any openings, six beams with tension-zone openings, and six beams with shear-zone openings were tested. It was found that the samples with tension-zone openings were slightly affected by the opening, where the reduction in the ultimate strength was approximately 7 to 14%. The beams were able to recover up to 46% of the lost strength by CFRP strengthening. On the other hand, the shear-zone opening significantly decreased the strength and energy absorption and increased the blast response. It can be concluded that it is not recommended to drill any opening at the shear zone as strength loss can reach 57% even with the strengthening, especially for blast resisting structure; in addition, the strength recovered from approximately 11.95 to 32.46% only. The finite element model was able to predict the strength of the beams. The results were closer in the case of tension-zone opening than those in the case of the shear-zone opening. Shear cracks were observed at the corners of the openings even if the opening exists at the tension zone. A reduction in the density of cracks can be observed after the strengthening, where the FRP sheet decreases the stress in the concrete.

Targeting autophagy to modulate hepatic ischemia/reperfusion injury: A comparative study between octreotide and melatonin as autophagy modulators through AMPK/PI3K/AKT/mTOR/ULK1 and Keap1/Nrf2 signaling pathways in rats.

Hepatic ischemia-reperfusion (HIR) injury is a common pathophysiological process in many clinical settings. This study was designed to compare the protective role of octreotide (somatostatin analogue, OCT) and melatonin (N-acetyl-5-methoxytryptamine, MLT) through the modulation of autophagy against HIR injury in rats. Male albino rats were divided into sham, HIR, OCT at three doses (50, 75, and 100 µg/kg), MLT, MLT + OCT75, compound C (AMPK inhibitor, CC), and CC + OCT75 groups. Ischemia was induced for 30 min followed by 24 h reperfusion. Biochemical, histopathological, immunohistochemical, lipid peroxidation, ELISA, qPCR, and western blot techniques were performed in our study. Liver autophagy was restored by OCT at doses (50 or 75 µg/kg) as indicated by elevating the expressions of Beclin-1, ATG7, and LC3 accompanied by the reduction of p62 expression through induction of AMPK/S317-ULK1 and inhibition of PI3K/AKT/mTOR/S757-ULK1 signaling pathways. As well, OCT maintained the integrity of the Keap1-Nrf2 system for the normal hepatic functions via controlling the Keap1 turnover through autophagy in a p62-dependent manner, resulting in upholding a series of anti-oxidant and anti-inflammatory cascades. These effects were abolished by compound C. On the other hand, MLT showed a decrease in the autophagy markers via inhibiting AMPK/pS317-ULK1 and activating PI3K/AKT/mTOR/pS757-ULK1 pathways. Autophagy inhibition with MLT markedly reversed the hepatoprotective effects of OCT75 after HIR injury. Finally, our results proved for the first time that OCT75 was more effective than MLT as it was sufficient to induce protective autophagy in our HIR model, which led to the induction of Nrf2-dependent AMPK/autophagy pathways.

Ocular films versus film-forming liquid systems for enhanced ocular drug delivery.

The short residence time, corneal barrier functions, and other effective eye protective mechanisms limited the ocular availability after topical application. Ocular inserts are being developed as polymer films for insertion into the conjunctival sac with the goal of increasing ocular availability. Unfortunately, these devices are not convenient for patients and are associated with many problems. The use of in situ gel/film-forming systems may provide promising alternative with comparable efficacy but this requires verification. Therefore, the current study compared ocular inserts with in situ film-forming liquids containing the same polymer components for ocular delivery of pilocarpine nitrate. Solvent casting technique was employed to prepare the inserts using and polyvinyl alcohol (PVA) as film-forming polymer blended with sodium alginate, as bioadhesive polymer. The effect of addition of either carboxymethycellulose, carbopol, polyvinylpyrrolidone, or methylcellulose was investigated. Solid-state characterization of the inserts indicated compatibility of the drug with film component. All inserts were of acceptable bioadhesive parameters and folding endurance that depended on the film composition. In vitro release studies reflected matrix diffusion kinetics for the film and liquid formulations. This confirms the in situ gelation of liquids. The calculated in vivo miotic pharmacokinetics parameters, using albino rabbits, reflected a better rank for the film but the difference was not statistically different from the in situ gel/film-forming systems. Ocular safety, as reflected by tear volume test, indicated acceptable safety of both liquid and inserts to the eye. The study suggested comparable efficacy of film-forming liquids to that of ocular films. Graphical abstract.

Metformin potentiates the chemotherapeutic effects of doxorubicin on 2-amino-1-methyl-6-phenylimidazo[4,5b] pyridine-induced Mammary Carcinoma in rats.

This study was carried out to evaluate the antitumor activity of Metformin (Met) and its impending utility to potentiate the chemotherapeutic action of doxorubicin on 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP)-induced rat mammary carcinogenesis. Female Sprague -Dawley (SD) rats were divided into seven groups (n = 15 each). Mammary carcinogenesis was induced by the administration of PhIP at a dose of 75 mg/kg by gavage. Met treatment was 2 mg/ml in drinking water for 26 weeks started after the last PhIP dose. Doxorubicin (Dox) treatment started after one month of the last PhIP dose with a dose of 4 mg/kg, i.v. once per week for 4 weeks. Compared to the PhIP group, the latency period of tumors in the PhIP+Dox, PhIP+Met, and PhIP+Dox+Met groups were significantly increased and tumors' incidences and multiplicities were significantly reduced. By immunohistochemistry, carcinomas from the combination treatment groups showed a significant decrease in the labeling indexes (LI%) of cellular proliferation and CD44 compared to the PhIP group while LI% for ERα was significantly decreased in all combination treatment groups compared to the PhIP-administered group. Moreover, the quantitative mRNA expression of ERα was significantly decreased in mammary tumors from PhIP + Dox+Met combined group more than the PhIP + Dox group. However, mRNA expression of EGF was found significantly lower in all combination treatment groups compared to the PhIP group. These findings suggest that Metformin potentiate the antitumor efficacy of doxorubicin and had beneficial effects on PhIP-induced mammary carcinogenesis through the prevention of cellular proliferation and mRNA expression of ERα and EGF.

Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury.

BACKGROUND AND AIM: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75µg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner. METHODS: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. RESULTS: OCT pretreatment at doses (50 or 75 µg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. CONCLUSION: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.

The potential beneficial effects of sildenafil and diosmin in experimentally-induced gastric ulcer in rats.

OBJECTIVES: research in the treatment of gastric ulcer has involved the investigation of protective drugs. These drugs may be used as adjacent therapy with the traditional pharmacologic treatment of peptic ulcer. The present study is designed to investigate the gastro protective effects of diosmin (DIO), sildenafil (SILD) and their combinations with ranitidine (RANT) against indomethacin (INDO)-induced gastric ulcer in rats. Additionally, the potential mechanisms of their effect are addressed. METHODS: DIO (100 mg/kg) and SILD (10 mg/kg) were administered by oral route for seven days prior to ulcer induction. Moreover, other rats were treated with RANT (50 mg/kg) not only to compare efficiency of the medications but also, to help clarify potential mechanisms of their effect. Following, after 24 h of fasting, INDO (100 mg/kg) was administered for induction of gastric ulcer. Furthermore, rats in each group were sacrificed 4 h later. Biochemical analysis of DIO, SILD, RANT and their combinations pre-treated host tissues demonstrated reduction in tumor necrosis factor (TNF)-α and malondialdehyde (MDA) contents and concomitant increase in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. RESULT: It is observed, that SILD and DIO pre-treatment showed non-significant effect on gastric juice PH. However, their combinations with RANT is superior to using RANT alone. In addition, the results revealed, that combinations of (RANT and SILD) and (RANT and DIO) showed the highest increase in gastric tissue NO levels. But, these two combinations achieved the lowest MDA levels relative to the control (INDO) group. Despite, all groups displayed non-significant effect on reduced GSH content, (RANT and SILD) group increased GSH concentration by 39.75% relative to INDO group. In addition, DIO, RANT and (RANT and DIO) pre-treatment have anti-apoptotic activity on gastric mucosa. On the other hand, SILD did not affect caspase-3 immunostaining. These results are confirmed by histopathological findings. CONCLUSION: The work outcomes provide a new gastro protective agents in clinical gastropathy. So, this study not only provides an efficient way for peptic ulcer protection, but also it may be considered for future studies in ulcer healing and gastric cancer.

Targeting MDR-1 gene expression, BAX/BCL2, caspase-3, and Ki-67 by nanoencapsulated imatinib and hesperidin to enhance anticancer activity and ameliorate cardiotoxicity.

There is a great demand to introduce new approaches into cancer treatment field due to incidence of increased breast cancer all over the world. The current study was designed to evaluate the role of imatinib mesylate (IM) and/or hesperidin (HES) nanoparticles alone or in combination in enhancing the anticancer activity and to investigate the ability of nanoencapsulation to reduce cardiotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. IM and HES were loaded into PLGA (poly(lactic-co-glycolic acid) polymer. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n = 10). On day 28 from tumor inoculation, mice were sacrificed and blood samples were collected in heparinized tubes for hematological studies, biochemical determination of lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (SGOT) levels. In addition, tumor and cardiac tissues were utilized for histopathological examination as well as determination of MDR-1 gene expression. Immunohistochemical staining of BAX and BCL-2 was done. Nano IM- and/or Nano HES-treated groups showed a significant reduction in tumor volume, weight, hematological, cardiac markers, and tumor MDR-1 gene downregulation compared to free conventional treated groups. In conclusion, the use of HES as an adjuvant therapy with IM could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, nanoencapsulation of IM and/or HES with PLGA polymer showed a remarkable anticancer activity.

Enhanced anticancer activity of combined treatment of imatinib and dipyridamole in solid Ehrlich carcinoma-bearing mice.

The current study was designed to evaluate potential enhancement of the anticancer activity of imatinib mesylate (IM) with dipyridamole (DIP) and to investigate the underlying mechanisms of the combined therapy (IM/DIP) to reduce hepatotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into seven groups (n = 10): SEC vehicle, IM50 (50 mg/kg), IM100 (100 mg/kg), DIP (35 mg/kg), a combination of IM50/DIP and IM100/DIP. On day 28th, mice were sacrificed and blood samples were collected for hematological studies. Biochemical determination of liver markers was evaluated. Glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP) levels were assessed. In addition, MDR-1 gene expression and immunohistochemical staining of BAX and BCL-2 was done. Also, in vitro experiment for determination of IC50 of different treatments and combination index (CI) were assessed in both MCF-7 and HCT-116 cell lines. IM- and/or DIP-treated groups showed a significant reduction in tumor volume, weight, and serum levels of SGOT, SGPT, and AIP compared to vehicle group. In addition, reduction of VEGF, Ki67, and adenosine contents was also reported by treated groups. Also, IM/DIP combination showed lower IC50 than monotherapy. Combination index is less than 1 for IM/DIP combination in both cell lines. DIP as an adjuvant therapy potentiated the cytotoxic effect of IM, ameliorated its hepatic toxicity, and showed synergistic effect with IM in vitro cell lines. Furthermore, the resistance against IM therapy may be overcome by the use of DIP independent on mdr-1 gene expression.

Daclatasvir and Sofosbuvir Mitigate Hepatic Fibrosis Through Downregulation of TNF-α / NF-κB Signaling Pathway.

BACKGROUND: Hepatic fibrosis is the major issue in chronic liver diseases such as chronic hepatitis C virus (HCV). The newly approved direct acting antiviral (DAA) agents such as Sofosbuvir (SOF) and daclatasvir (DAC) have been found to be associated with decreased fibrotic markers in HCV patients. AIM: This study tried to explore whether the reported antifibrotic effect of these drugs is antiviral dependent or drug induced. METHOD: Hepatic fibrosis was induced by (0.5ml/kg) CCl4 IP twice a week for six weeks. SOF (20 mg/kg/d) and DAC (30 mg/kg/d) were added in the last four weeks of treatments. Liver functions, fibrotic markers such as Hyaluronic acid and metalloproteinase-9 were detected using immunoassay. The expression of TNF-α/NF-κB signaling pathway as well as Bcl-2 were done using immunoassay. RESULTS: SOF and DAC exerted a potent antifibrotic effect evidenced by their activity against hyaluronic acid HA and metalloproteinase MMP-9 significantly (P≤0.001). This effect was further proved histopathologically where liver tissues from rats treated by drugs showed marked inhibition of collagen precipitation as well as inhibition of HSCs activation. This antifibrotic action was associated with decreased expression of TNF-α /NF-κB signaling pathway and induction of Bcl-2. CONCLUSION: SOF/ DAC antifibrotic effect is independent of its antiviral activity. The molecular events associated with this effect were the downregulation of TNF-α / NF-κB signaling pathway and induction of Bcl-2.

Comparative effects of enalapril versus perindopril on serum levels of leptin and adiponectin in hypertensive patients.

Introduction: Abnormal adipokine levels affect blood pressure (BP) regulation. Hypo-adiponectinaemia and hyperleptinaemia were reported in hypertension, little is known about how antihypertensive therapy affects these alterations. This study aimed to evaluate the effects of perindopril versus enalapril on plasma adiponectin, tumour necrosis alpha (TNF-α) and leptin levels in hypertensive individuals.Methods: In the present study, we analysed the samples obtained from 93 treatment-naive, adult hypertensive patients, randomised to treatement with enalapril (10 mg/d, n = 31), perindopril (5 mg/d, n = 31), or maintained on life style modification (n = 31). Plasma levels of leptin, adiponectin, TNF-α and lipid profile were determined at baseline, and after 3 months.Results: Compared to subjects maintained on lifestyle modification (n = 31), enalapril or perindopril treatment was associated with a significant decrease in BP. Administration of perindopril or enalapril resulted in an increase in plasma adiponectin and a reduction in plasma leptin. No significant changes in lipid profile were observed after treatment.Conclusions: Our results indicate that perindopril is superior to enalapril when it comes to its effect on the human adipose-tissue-derived hormones. This suggests that angiotensin-converting enzyme inhibitors improves the adipokine profile, possibly allowing beneficial effects to hypertensive individuals.

Protective effects of mirtazapine and chrysin on experimentally induced testicular damage in rats.

Mirtazapine is an antidepressant with prominent antioxidant effects. Chrysin, a natural flavone, exhibits multiple pharmacological actions. This study was designed to investigate the potential protective effects of chrysin and mirtazapine against nitrofurazone-induced testicular damage in rats. Possible underlying mechanisms such as oxidative stress, inflammation and apoptosis were also investigated. Testicular damage was induced by oral administration of nitrofurazone (50mg/kg/day) for two weeks. Chrysin (25 and 50mg/kg/day, p.o.) and mirtazapine (15 and 30mg/kg/day, p.o.) were applied for three weeks, starting one week before nitrofurazone administration. Prophylactic treatment with chrysin and mirtazapine attenuated the elevation of serum acid phosphatase enzyme activity and halted the decline of sperm count and sperm viability resulted from nitrofurazone administration. Moreover, both agents ameliorated nitrofurazone-induced lipid peroxidation, glutathione depletion, elevation in tumor necrosis factor-α level and reduction in c-kit level in rat testes. With respect to apoptosis, immunohistochemical analysis revealed that chrysin and mirtazapine reduced the expression of caspase-3 in testicular tissue which was induced by nitrofurazone. Histopathological findings further supported the protective effects of both drugs against nitrofurazone-induced testicular injury. These findings suggest that the cytoprotective effects of chrysin and mirtazapine on rat testes were associated with suppression of oxidative stress and apoptotic tissue damage. Generally, chrysin prophylactic treatment showed a superior testicular protection than mirtazapine at the tested doses.

Oxamate potentiates taxol chemotherapeutic efficacy in experimentally-induced solid ehrlich carcinoma (SEC) in mice.

Several human cancers including the breast display elevated expression of Lactate dehydrogenase-A (LDH-A), the enzyme that converts pyruvate to lactate and oxidizes NADH to NAD+. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate also plays roles in promoting tumor inflammation and as a signaling molecule that stimulates tumor angiogenesis. Because of its essential role in cancer metabolism, LDH-A has been considered as a potential target for combination cancer therapy. Therefore, the current study investigated the possible anti-tumor effect of LDH inhibitor (oxamate) in a murine model of breast cancer [Solid Ehrlich Carcinoma (SEC)], alone and in combination with Taxol chemotherapy. The potential underlying mechanisms were also investigated. The results indicated that oxamate induced significant anti-tumor activity against the SEC. Mechanistically, the combination treatment was more efficient than paclitaxel monotherapy in reducing ATP, MDA, TNF-α and Il-17 contents in SEC. Moreover, the apoptotic and anti-angiogenic effects of the combination treatment were triggered more efficiently as compared to paclitaxel monotherapy, Therefore, oxamate may represent a promising agent that enhance the antitumor activity of paclitaxel.

Antifibrotic effect of diethylcarbamazine combined with hesperidin against ethanol induced liver fibrosis in rats.

Chronic alcohol consumption leads to extracellular matrix hyperplasia and liver fibrosis with a great role of hepatic stellate cell (HSC) activation in this process. The present study was designed to investigate the possible protective effects of diethylcarbamazine (DEC) (50mg/kg, acting as an anti-inflammatory drug, interferes with the arachidonic acid metabolism) when administrated in combination with hesperidin (HDN) (200mg/kg, a flavanone glycoside with potent antioxidant and anti-inflammatory activities) against alcoholic liver fibrosis in wistar rats compared to silymarin (Sil) (100mg/kg). Liver fibrosis was induced in rats using ethanol (EtOH) (1ml/100g/day, p.o.) twice a week for seven weeks. Then, tissue and blood samples were collected to assess the protective effect of DEC+HDN combination. Our results indicated that DEC when combined with HDN blunted EtOH-induced necroinflammation and elevation of liver injury parameters in serum. Besides, attenuated EtOH- induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both DEC and HDN were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) inhibiting the activation of NF-κB as indicated by preventing release of hepatic IL6; (3) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing a-smooth muscle actin (a-SMA) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting serum transforming growth factor-b1 (TGF-b1). Our study indicates a novel hepatoprotective effect when DEC was co-administered with HDN against liver fibrosis.

Combination of tadalafil and diltiazem attenuates renal ischemia reperfusion-induced acute renal failure in rats.

Life threatening conditions characterized by renal ischemia/reperfusion (RIR) such as kidney transplantation, partial nephrectomy, renal artery angioplasty, cardiopulmonary bypass and aortic bypass surgery, continue to be among the most frequent causes of acute renal failure. The current study investigated the possible protective effects of tadalafil alone and in combination with diltiazem in experimentally-induced renal ischemia/reperfusion injury in rats. Possible underlying mechanisms were also investigated such as oxidative stress and inflammation. Rats were divided into sham-operated and I/R-operated groups. Anesthetized rats (urethane 1.3g/kg) were subjected to bilateral ischemia for 30min by occlusion of renal pedicles, then reperfused for 6h. Rats in the vehicle I/R group showed a significant (p˂0.05) increase in kidney malondialdehyde (MDA) content; myeloperoxidase (MPO) activity; TNF-α and IL-1ß contents. In addition significant (p˂0.05) increase in intercellular adhesion molecule-1(ICAM-1) content, BUN and creatinine levels, along with significant decrease in kidney superoxide dismutase (SOD) activity. In addition, marked diffuse histopathological damage and severe cytoplasmic staining of caspase-3 were detected. Pretreatment with combination of tadalafil (5mg/kg bdwt) and diltiazem (5mg/kg bdwt) resulted in reversal of the increased biochemical parameters investigated. Also, histopathological examination revealed partial return to normal cellular architecture. In conclusion, pretreatment with tadalafil and diltiazem combination protected against RIR injury.

Celecoxib and omega-3 fatty acids alone and in combination with risperidone affect the behavior and brain biochemistry in amphetamine-induced model of schizophrenia.

The implications of oxidative stress and neuro-inflammation in the pathogenesis of schizophrenia have been elucidated. Despite their effectiveness against positive symptoms of schizophrenia, antipsychotics have limited effectiveness against negative and cognitive symptoms and are associated with remarkable adverse effects. The use of celecoxib or omega-3 in schizophrenia may have beneficial effects. This study aimed to evaluate the possible efficacies of celecoxib, omega-3 or the combination of celecoxib+risperidone and omega-3+ risperidone compared to risperidone on the behavior and brain biochemistry in rats. In the present study, an amphetamine-induced model of schizophrenia in adult male rats was used to evaluate the effects of celecoxib, omega-3, celecoxib+risperidone and omega-3+ risperidone on the behavior of animals and on brain lipid peroxidation or tumor necrosis factor-alpha. In the water maze task, celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone significantly decreased the latency time compared to amphetamine-treated group. Celecoxib, omega-3, celecoxib+risperidone, omega-3+risperidone also significantly reversed the decreased spontaneous alternation induced by amphetamine in the Y-maze task. In the social interaction task, groups treated with celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone spent less time to recognize foreign animals than animals in the amphetamine-treated group. Increased brain MDA and TNF-α levels due to amphetamine were significantly reduced in groups treated with celecoxib+risperidone or omega-3+ risperidone. The present findings showed that celecoxib or omega-3 can attenuate amphetamine- induced behavioral impairment and these effects may be associated with their ability to decrease lipid peroxidation and cytokine release. Celecoxib or omega-3 may be promising candidates as adjuvant therapy for schizophrenia.

Rebamipide retards CCl4-induced hepatic fibrosis in rats: Possible role for PGE2.

Prostaglandin E2 (PGE2) is a potent physiological suppressor of liver fibrosis. Because the anti-ulcer drug rebamipide can induce the formation of endogenous PGE2, this study investigated the potential effects of rebamipide on development of a hepatic fibrosis that was inducible by carbon tetrachloride (CCl4). Groups of Wistar rats received intraperitoneal (IP) injections of CCl4 (0.45 ml/kg [0.72 g CCl4/kg]) over the course of for 4 weeks. Sub-sets of CCl4-treated rats were also treated concurrently with rebamipide at 60 or 100 mg/kg. At 24 h after the final treatments, liver function and oxidative stress were indirectly assessed. The extent of hepatic fibrosis was evaluated using two fibrotic markers, hyaluronic acid (HA) and pro-collagen-III (Procol-III); isolated liver tissues underwent histology and were evaluated for interleukin (IL)-10 and PGE2 content. The results indicated that treatment with rebamipide significantly inhibited CCl4-induced increases in serum ALT and AST and also reduced oxidative stress induced by CCl4. Fibrotic marker assays revealed that either dose of rebamipide decreased the host levels of Procol-III and HA that had become elevated due to the CCl4. At the higher dose tested, rebamipide appeared to be able to permit the hosts to have a normal liver histology and to minimize any CCl4-induced collagen precipitation in the liver. Lastly, the use of rebamipide was seen to be associated with significant increases in liver levels of both PGE2 and the anti-inflammatory cytokine IL-10. Based on these findings, it is concluded that rebamipide can retard hepatic fibrosis induced by CCl4 and that this effect may, in part, be mediated by an induction of PGE2 and IL-10 in the liver itself.