Donepezil and quercetin alleviate valproate-induced testicular oxidative stress, inflammation and apoptosis: Imperative roles of AMPK/SIRT1/ PGC-1α and p38-MAPK/NF-κB/ IL-1ß signaling cascades.

The mounting evidence of valproate-induced testicular damage in clinical settings is alarming, especially for men taking valproate (VPA) for long-term or at high doses. Both donepezil (DON) and quercetin (QUE) have promising antioxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, this study aimed to determine whether DON, QUE, and their combination could mitigate VPA-induced testicular toxicity and unravel the mechanisms underlying their protective effect. In this study, male albino rats were randomly categorized into six equal groups: control, VPA (500 mg/kg, I.P., for 14 days), DON (3 and 5 mg/kg), QUE (50 mg/kg), and DON 3 + QUE combination groups. The DON and QUE treatments were administered orally for 7 consecutive days before VPA administration and then concomitantly with VPA for 14 days. VPA administration disrupted testicular function by altering testicular architecture, ultrastructure, reducing sperm count, viability, and serum testosterone levels. Additionally, VPA triggered oxidative damage, inflammatory, and apoptotic processes and suppressed the AMPK/SIRT1/PGC-1α signaling cascade. Pretreatment with DON, QUE, and their combination significantly alleviated histological and ultrastructure damage caused by VPA and increased the serum testosterone level, sperm count, and viability. They also suppressed the oxidative stress by reducing testicular MDA content and elevating SOD activity. In addition, they reduced the inflammatory response by suppressing IL-1ß level, NF-κB, and the p38-MAPK expression as well as inhibiting apoptosis by diminishing caspase-3 and increasing Bcl-2 expression. These novel protective effects were mediated by upregulating AMPK/SIRT1/PGC-1α signaling cascade. In conclusion, these findings suggest that DON, QUE, and their combination possess potent protective effects against VPA-induced testicular toxicity.

Tiron ameliorates acetic acid-induced colitis in rats: Role of TGF-ß/EGFR/PI3K/NF-κB signaling pathway.

BACKGROUND: Ulcerative colitis (UC), an ongoing inflammatory disorder of the colon, is marked by persistent mucosal surface irritation extending from the rectum to the near-proximal colon. Tiron is a synthetic analogue of vitamin E which is known to have antioxidant and anti-inflammatory effects in various animal models, so the goal of this study was to find out whether Tiron had any preventive impacts on UC inflicted by acetic acid (A.A) exposure in rats. METHOD: Tiron (235 and 470 mg/kg) was administered intra-peritoneally for 2 weeks, and A.A (2 ml, 3 % v/v) was injected intra-rectally to cause colitis. Colon tissues and blood samples were then collected for measurement of various inflammatory and oxidative stress biomarkers. RESULTS: Tiron administration significantly diminished lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon as compared to A.A-injected rats. Additionally, Tiron attenuated oxidative stress biomarkers. Tiron also enforced the levels of Glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3), while it greatly lowered the expression of nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interferon-γ (IFN-γ), and transforming growth factor-1(TGF-ß1), phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic cellular structures. Furthermore, colonichistopathologic damages, revealed by hematoxylin and eosin (H&E) and Alcian Blue stain, were significantly decreased upon Tiron administration. CONCLUSION: Tiron prevented A.A-induced colitis in rats via modulating inflammatory pathway TGF-ß1/P-EGFR/PI3K/AKT/NF-κB, alongside managing the oxidant/antioxidant equilibrium, and boosting the reliability of the intestinal barrier.

Eicosapentaenoic acid mitigates ulcerative colitis-induced by acetic acid through modulation of NF-κB and TGF-ß/ EGFR signaling pathways.

BACKGROUND: Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine that mostly affects the rectum and colon. The absence of safe and effective therapeutic agents encourages the discovery of novel therapeutic agents to effectively treat UC and its complications. The purpose of this research was to examine the protective impact of Eicosapentaenoic acid (EPA) in rats with UC induced by acetic acid (AA). METHOD: AA (2 ml, 3 % v/v) was injected intrarectally to cause UC. Before administering AA, EPA (300 and 1000 mg/kg) was given orally for 28 days. RESULTS: EPA inhibited AA-induced UC by enhancing colonic histopathological changes like inflammation, goblet cell loss, glandular hyperplasia and mucosal ulceration, concomitant with a reduction in colon weight, colon weight/length ratio, C-reactive protein (CRP), and serum lactate dehydrogenase (LDH). EPA also effectively restored the imbalance between oxidants and antioxidants caused by AA. In addition, EPA increased the levels of trefoil factor-3 (TFF-3) and glucagon-like peptide-1 (GLP-1), while significantly reducing the expression of nuclear factor kappa B (NF-κB), interferon-γ (IFN-γ), and interleukin-6 (IL-6), transforming growth factor-1(TGF-ß1), and phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic tissues. CONCLUSION: EPA inhibited AA-induced UC in rats by modulating the TGF-ß/P-EGFR and NF-κB inflammatory pathways, regulating the oxidant/antioxidant balance, and enhancing the colon barrier integrity.

Potential effects of carbon monoxide donor and its nanoparticles on experimentally induced gastric ulcer in rats.

The prevalence of gastric ulcers is increasing worldwide, especially those brought on by non-steroidal anti-inflammatory drugs (NSAIDS), so prevention is extremely crucial. The protective potential of carbon monoxide (CO) in several inflammatory disorders has been clarified. The goal of the current study was to investigate the gastroprotective effect of CO produced by its pharmacological donor (CORM2) and its nanoparticles (NPs) against indomethacin (INDO)-induced ulcers. Investigations on CORM2's dose-dependent effects were also conducted. For induction of gastric ulcer, 100 mg kg-1 of INDO was given orally. Before ulcer induction, CORM2 (5, 10, and 15 mg kg-1), CORM2 nanoparticles (5 mg kg-1), or ranitidine (30 mg kg-1) were given intraperitoneally for 7 days. Ulcer score, gastric acidity, gastric contents of malondialdehyde (MDA), nitric oxide (NO), heme oxygenase-1 (HO-1), and carboxyhemoglobin (COHb) blood content were estimated. Additionally, gene expression of nuclear factor erythroid 2-related factor 2 (NRF2) and immunohistochemical staining of cyclooxygenase-1 (COX-1) as well as cyclooxygenase-2 (COX-2) were analyzed. Results demonstrated a substantial dose-dependent decrease in ulcer score, pro-inflammatory indicators, and oxidative stress markers with CORM2 and its NPs. Furthermore, CORM2 and its NPs markedly increased NRF2, COX-1, and HO-1, but CORM2 NPs outperformed CORM2 in this regard. In conclusion, the CO released by CORM2 can protect against INDO-induced gastric ulcers dose dependently, and the highest used dose had no effect on COHb concentration.

Combined carvacrol and cilostazol ameliorate ethanol-induced liver fibrosis in rats: Possible role of SIRT1/Nrf2/HO-1 pathway.

Carvacrol is a natural phenolic monoterpenoid, and cilostazol is a selective phosphodiesterase-3 inhibitor with antioxidant, anti-inflammatory and antiapoptotic effects. This experiment aimed to explore the hepatoprotective effects of carvacrol and cilostazol alone and in combination against alcoholic liver fibrosis (ALF), and the underlying mechanisms, using silymarin as a reference anti-fibrotic product. ALF was induced by oral administration of ethanol (1 ml/100 g/day) thrice per week. Silymarin (100 mg/kg), carvacrol (70 mg/kg), cilostazol (50 mg/kg), or carvacrol + cilostazol combination were administered daily and concurrently with ethanol for six weeks. Hepatic changes were evaluated by quantifying serum biomarkers of liver injury, hepatic MDA, GSH and NOx as oxidative stress markers, interleukin (IL)-10 as an anti-inflammatory cytokine, 4-hydroxyproline (4-HYP) as a collagen synthesis indicator, transforming growth factor (TGF)-ß1 as a profibrogenic cytokine, α-smooth muscle actin (α-SMA) as a marker of hepatic stellate cells (HSCs) activation, histopathological (necroinflammation and fibrosis) scores and hepatic sirtuin-1 (SIRT1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1) mRNA levels. Our results showed that carvacrol, cilostazol, and their combination significantly ameliorated ethanol-induced hepatic fibrosis manifested as improving hepatic functions and histopathological features, attenuating α-SMA immunostaining, reducing TGF-ß1 and 4-HYP levels, suppressing oxidativeinjury and elevating IL-10 contents. Such effects were accompanied by upregulating SIRT1, Nrf2 and HO-1 genes. This work disclosed for the first time the hepatoprotective effect of carvacrol against ALF and, to a greater extent, with carvacrol + cilostazol combination that could be partially accredited to SIRT1/Nrf2/HO-1 pathway with consequent antioxidant, anti-inflammatory, and anti-fibrotic features.

LC-MS/MS metabolomics profiling of Glechoma hederacea L. methanolic extract; in vitro antimicrobial and in vivo with in silico wound healing studies on Staphylococcus aureus infected rat skin wound.

LC-MS/MS analysis of Glechoma hederacea L. methanolic extract (GHME), revealed the identification of 25 metabolites. Ursolic acid (1), 2α-hydroxyursolic acid or corosolic acid (2), 2ß-hydroxyursolic acid or epi-corosolic (3), luteolin 7-O-ß-D-glucopyranoside (4) and rosmarinic acid (5) were isolated and identified using spectroscopy. Antibacterial activity of GHME against multi drug resistance Staphylococcus aureus clinical isolates was measured. Minimum inhibitory concentrations (MICs) were ranged from 62.5 to 500 µg/ml. In vivo wound healing potential of 2%, and 5% GHME prepared hydrogels were criticized on Staphylococcus aureus infected wound rat model. 5% GHME prepared hydrogel treated group showed significant (p < 0.05) shrinkage of their colony forming unit/ml (CFU/ml) values in comparison with standard Fucidin. Meanwhile, wound closure associated with full re-epithelization and hair follicles proliferation was noticed after ten days of treatment. Finally, among the GHME isolated compounds, luteolin 7-O-ß-D-glucopyranoside (4) exhibited the highest molecular docking score (-9.6 kcal/mol) against matrix metalloproteinase-8 target (MMP-8).

Comparative study between effects of ginkgo biloba extract and extract loaded on gold nanoparticles on hepatotoxicity induced by potassium bromate.

In human organs, potassium bromate (KBrO3) produces toxicity. The main causes of KBrO3 hepatotoxicity are the formation of reactive oxygen species (ROS) and DNA damage. The purpose of this study is to show how ginkgo biloba extract (GBE) and extract loaded with nanogold particles (GBE@AuNPs) affect hepatotoxicity caused by KBrO3. The rats were separated into eight groups: control (group I), GBE (group II), AuNPs (group III), GBE@AuNPs (group IV), KBrO3 (group V), KBrO3 and GBE (group VI), KBrO3 and AuNPS (group VII), and KBrO3 and GBE@AuNPs (group VIII). KBrO3 generated DNA damage spots in a comet assay, which were associated with increased inflammatory indicators (IL-6), decreased anti-apoptotic Bcl-2, and increased apoptotic markers (Bax and caspase-3). The inflammatory, apoptotic, and ultrastructural alterations in liver tissue produced by KBrO3 were reduced in treated groups VI, VII, or VIII. The hepatotoxic effects of KBrO3 were reduced when GBE, AuNPs, or GBE@AuNPs were used; the particular GBE@AuNPs were the most effective.

Tissue distribution, placental transfer and excretion of silver nanoparticles in pregnant rats after a single oral dose.

A quantitative assessment of silver nanoparticles (AgNPs) in fluids and some organs of pregnant rats as well as their fetal blood were carried out in this study. A single oral dose (1mg/kg) of AgNPs with a size range of 4-20 nm was administered to pregnant rats on the 19th of gestation. Five groups were euthanized after 10 min, 1, 6, 12, and 24 hr as well as the control group. Total Silver (Ag) contents were measured in bloods (maternal and fetal) and several organs using Inductive Coupled Plasma Optical Emission Spectroscopy (ICP-OES) followed by acid digestion. In maternal blood, AgNPs were found to increase time-dependently after 12 and 24 hr into 0.135 and 0.224 µg/ml, but it was slightly higher in fetal blood (0.32 and 0.31 µg/ml) after 10 min and 1 hr. In other samples: kidneys, liver, spleen, placenta, and uterus the data indicated that NPs were rapidly absorbed from the dosing site (gastrointestinal tract) as evidenced by the detection of Ag in the analyzed samples (fluids and tissues). On the other hand, the cumulative percentages of excretion level in urine was 8.25% which was higher than in feces (4.77%) after 24 hr. These findings indicate the ability of AgNPs to accumulate in pregnant rats and transfer to their fetus imposing adverse outcomes and male formation. Thus, further investigations must be followed for direct and/or indirect exposure to such NPs before decision for their practices.

Protective role of irbesartan against cyclophosphamide-induced testicular damage in rats via up-regulating PPAR-γ signaling and ameliorating NF-κB/NLRP3/IL-18 inflammatory axis.

BACKGROUND: Cancer and its therapies can impact fertility in various ways, and therefore a growing number of cancer survivors face fertility as a significant concern. The cytotoxic alkylating agent cyclophosphamide (CP) is commonly used as an antineoplastic agent; unfortunately, its use is significantly associated with male infertility and damage to the reproductive system. AIM: The present study aimed to assess the possible beneficial effects of Irbesartan (IRB) in a rat model of CP-induced testicular toxicity. MAIN METHODS: The effects of treatment were assessed by measuring peroxisome proliferator-activated receptor gamma (PPAR-γ) expression via qRT-PCR, the immunohistochemical (IHC) assessment of apoptotic markers, NOD-like receptor protein 3 (NLRP3), and nuclear factor-κB (NF-κB), determination of the count and viability of epididymal sperm, oxidative stress markers via biochemical analysis, serum testosterone, caspase-1, and interleukin-18 (IL-18) levels via ELISA, histopathological assessment, and fibrosis by Masson's trichrome (MT) stain. KEY FINDINGS: There was a significant increase in malondialdehyde (MDA), caspase-1, and IL-18 contents, NF-κB, NLRP3, Bcl-2-associated X protein (Bax), caspase-3, and MT staining in testicular tissue after CP administration compared to the normal control group. Whereas reduced glutathione (GSH), superoxide dismutase (SOD), PPAR-γ expression, B-cell lymphoma-2 (Bcl-2) staining, serum testosterone, and the count and viability of epididymal sperm were decreased compared to the normal control group. The IRB treatment has reversed CP-induced testicular toxicity. SIGNIFICANCE: It is possible to conclude that IRB revealed a significant testicular protective effect against CP via antioxidant, anti-apoptotic, and anti-inflammatory effects.

Potassium bromate-induced nephrotoxicity and potential curative role of metformin loaded on gold nanoparticles.

Potassium bromate (KBrO3) is classified by the International Agency for Research on Cancer as a carcinogenic compound, where it causes renal tumors. The present study investigated the potential curative effect of metformin loaded on gold nanoparticles (MET AuNPs) in attenuating KBrO3-induced nephrotoxicity. Rats were divided into eight groups (control, MET, AuNPs, MET AuNPs, KBrO3, KBrO3/MET, KBrO3/AuNPS, and KBrO3/MET AuNPs). KBrO3 administration resulted in a significant elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), albumin (Alb), total bilirubin (TB), direct bilirubin (DB), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, urea, uric acid. Also, KBrO3 significantly increased renal malondialdehyde (MDA), protein carbonyl (PC), and nitric oxide (NO) levels and reduced the activities of antioxidant molecules superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and Reduced glutathione (GSH). It also caused damaged DNA spots in comet assay and increased inflammatory IL-6 and apoptotic markers (caspase 3, Bax) while antiapoptotic Bcl-2 was significantly reduced. MET, AuNPS, MET AuNPS reduced the extent of renal damage induced by KBrO3 as indicated by decreased (AST, ALT, ALP, Alb, TP, TB, DB, creatinine, urea, uric, Lipid profile). MET, AuNPS, MET AuNPS showed a good curative effect against KBrO3-induced nephrotoxicity and MET AuNPS group showed better results compared with monotherapy.

Zinc Supplementation in Preterm Neonates with Jaundice: Is it Beneficial?

BACKGROUND: Neonatal jaundice is a common neonatal disease that has adverse effects on neonates, especially preterm neonates, when indirect bilirubin level is adequately high to pass the blood-brain barrier, causing bilirubin encephalopathy or kernicterus. AIM: This study aimed to investigate the value of zinc (Zn) supplementation in preterm neonates with jaundice and whether it will be beneficial. PATIENTS AND METHODS: A prospective randomized clinical trial, with the identification number TCTR20200504007, was conducted at Tanta University Hospital from July 2016 to March 2018 on 200 preterm neonates with jaundice. The studied neonates were divided into two groups: group 1, which received Zn and phototherapy, and group 2, which received phototherapy only and did not receive Zn. In group 1, 100 preterm neonates with jaundice received Zn as 0.6 mL (cm3) of zinc origin/kg/day orally through the oro-nasogastric tube divided into two doses (every 12 h), which was equal to 1.2 mg elemental zinc/kg/day orally for 10 days. RESULTS: There was no significant difference in serum bilirubin level between the two groups on the 2nd, 4th, and 6th days of admission, while the serum bilirubin level was significantly decreased in group 1 compared with that in group 2 only on the 8th, 9th, and 10th days of admission. The p-- values were 0.045*, 0.027*, and 0.004*, respectively. CONCLUSION: Zn administration to preterm neonates with jaundice was found to be beneficial in decreasing serum bilirubin level. RECOMMENDATION: Zn supplementation should be provided to preterm neonates with jaundice.

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.

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.

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.

Role of cysteinyl leukotriene receptor-1 antagonists in treatment of experimentally induced mammary tumor: does montelukast modulate antitumor and immunosuppressant effects of doxorubicin?

It has been reported that a leukotriene (LT)-D4 receptor (i.e. cysteinyl LT1 receptor; CysLT1R) has an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (MON), a CysLT1R antagonist, in a mouse mammary carcinoma model, that is, a solid Ehrlich carcinoma (SEC). Effects of MON on tumor-induced immune dysfunction and the possibility that MON may modulate the antitumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several dosings with MON (10 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, intraperitoneal), were investigated in vivo; end points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that MON induced significant antitumor activity against the SEC. MON treatments also significantly mitigated both tumor- and DOX-induced declines in immune parameters assessed here. Moreover, MON led to decreased NF-κB nuclear expression and, in doing so, appeared to chemosensitize these tumor cells to DOX-induced apoptosis.

PPARγ-dependent anti-tumor and immunomodulatory actions of pioglitazone.

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to play important roles in carcinogenesis. The current study was carried out to assess the possible anti-tumor effects of pioglitazone (PIO), a PPARγ agonist, in a mouse mammary carcinoma model, i.e. a solid Ehrlich carcinoma (SEC). Effects of PIO on tumor-induced immune dysfunction, and the possibility that PIO may modulate the anti-tumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several doses of PIO (100 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, IP), was investigated in vivo; end-points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor (TNF)-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that PIO induced significant anti-tumor activity against the SEC. PIO treatments also significantly mitigated both tumor- and doxorubicin-induced declines in immune parameters assessed here. Moreover, PIO led to decreased NF-κB nuclear expression, and, in doing so, appeared to chemo-sensitize these tumor cells to DOX-induced apoptosis. All pioglitazone-studied effects were antagonized by GW9662, a selective PPARγ antagonist.