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Inflammatory microenvironment is known to accelerate the progression of malignant tumors. We investigated the possible anti-inflammatory effect of nicaraven on slowing tumor growth. Tumor-bearing mice randomly received nicaraven injection (50 mg/kg daily, i.p, n = 8) or placebo treatment (n = 8) for 10 days, and then sacrificed for evaluations. Nicaraven administration effectively inhibited the fast growth of tumor, as a large tumor (> 1.0 g) developed finally in three of the eight mice received placebo treatment. Cytokines/chemokines array indicated that nicaraven reduced the levels of CXCL10 and SDF-1 in the tumor as well as the levels of IL-2 and MIP-2 in serum. Immunofluorescence staining showed that nicaraven significantly reduced the recruitment of macrophages and neutrophils in the tumor. Interestingly, western blot indicated that the expression of CD86, CD206, and NIMP-R14 was especially enhanced in the three large-size tumors, suggesting the potential role of nicaraven in preventing the hyper-inflammatory tumor microenvironment. Moreover, the expression of PARP-1 was downregulated, but the expression of phospho-p38 MAPK, phospho-MKK-3/6, and phospho-MSK-1 was upregulated in the large-size tumors, suggesting the involvement of p38 MAPK pathway in the anti-inflammatory effect of nicaraven. Taken together, our study suggests that nicaraven may effectively prevent the fast growth of inflamed tumors by an anti-inflammatory mechanism.

Inflammatory microenvironment is known to accelerate the progression of malignant tumors. We investigated the possible anti-inflammatory effect of nicaraven on slowing tumor growth. Tumor-bearing mice randomly received nicaraven injection (50 mg/kg daily, i.p, n = 8) or placebo treatment (n = 8) for 10 days, and then sacrificed for evaluations. Nicaraven administration effectively inhibited the fast growth of tumor, as a large tumor ( 1.0 g) developed finally in three of the eight mice received placebo treatment. Cytokines/chemokines array indicated that nicaraven reduced the levels of CXCL10 and SDF-1 in the tumor as well as the levels of IL-2 and MIP-2 in serum. Immunofluorescence staining showed that nicaraven significantly reduced the recruitment of macrophages and neutrophils in the tumor. Interestingly, western blot indicated that the expression of CD86, CD206, and NIMP-R14 was especially enhanced in the three large-size tumors, suggesting the potential role of nicaraven in preventing the hyper-inflammatory tumor microenvironment. Moreover, the expression of PARP-1 was downregulated, but the expression of phospho-p38 MAPK, phospho-MKK-3/6, and phospho-MSK-1 was upregulated in the large-size tumors, suggesting the involvement of p38 MAPK pathway in the anti-inflammatory effect of nicaraven. Taken together, our study suggests that nicaraven may effectively prevent the fast growth of inflamed tumors by an anti-inflammatory mechanism.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with high sphingosine kinase 1(SPHK1) expression in the colon, however its role in pathogenesis of UC is not clearly understood so, the aim of the present study was to clarify the role of SPHK1 and investigate whether the anti-inflammatory effects of metformin in UC is mediated by Sphingosine kinase 1/sphingosine 1 phosphate (S1P) signaling pathway.Colitis was induced in adult male wistar rats by intra rectal administration of oxazolone in the fifth and seventh days from initial presensitization. Oxazolone treated rats were divided into untreated oxazolone group, metformin and mesalazine treated groups both in a dose of 100 mg/kg/day orally for 21 days. Along with these groups normal control and saline groups were used .Colitis was assessed by colon length, disease activity index (DAI) and histological examination of colontissue. Plasma samples were used to measure S1P.SPHK1 activity, signal transducer and activator of transcription -3(STAT-3), interleukin-6 (IL-6), nitric oxide (NO), myeloperoxidase activity (MPO), reduced glutathione (GSH) and tissue expression of intracellular cell adhesion molecule -1(ICAM-1) and caspase-3 genes were measured in tissue.Metformin successfully attenuated oxazolone colitis by increasing colon length, decreasing DAI and improved colon histologic picture. Metformin also induced a significant decrease in Plasma SIP, SPHK1 activity, inflammatory, oxidative stress markers, ICAM-1 and Caspase-3 genes expression compared to oxazolone group.It is revealed that metformin alleviated inflammation and underlying mechanism may result from inhibition of SPHK1/S1P signaling pathway.

Background: Alzheimer’s disease (AD), the most common cause for dementia, is an irreversible progressive neurodegenerative disorder. Aim: To investigate the potential protective role of Lamotrigine (LTG) and Gabapentin (GBP) either alone and in combination in Lipopolysaccride-induced Alzheimer's disease (AD) in mice. Materials and Methods: Mice were divided into 5 groups: Normal control group, Lipopolysaccride (LPS) group (animals were injected by single I.P. dose of LPS in a dose of 0.8 mg/kg), LTG group (animals were injected by single I.P. dose of LPS 0.8 mg/kg and received oral LTG 30 mg/kg/day), GBP group (animals were injected by single I.P. dose of LPS 0.8 mg/kg and received oral GBP 200 mg/kg/day) and LTG+GBP group (animals were injected by single I.P. dose of LPS 0.8 mg/kg and received both oral LTG 30 mg/kg/day and GBP 200 mg/kg/day), therapy started 2-h after LPS injection for 7 successive days. Novel object recognition and Y-maze tests were conducted. Brain homogenate used for the estimation of superoxide dismutase (SOD), acetylcholine esterase (AchE) activity, glutamate, reduced glutathione (GSH) and malonyialdehyde (MDA) contents. Results: LPS significantly induced neurobehavioral disturbances compared to normal control with significantly higher MDA, AchE and glutamate contents, with a reduction in SOD and GSH levels. Treatment with either LTG or GBP significantly ameliorated the effects of LPS injection on neurobehavioral tests, oxidative milieu with a significant reduction in AchE activity and glutamate content in favor of LTG. Combined therapy significantly improved both neurobehavioral testing and the estimated biochemical markers. Conclusion: GBP and/or LTG therapy improved neurobehavioral testing in LPS- induced AD in mice by restoring oxidant/antioxidant milieu with a concomitant reduction in AchE activity and glutamate content. Furthermore; the combination of both drugs resulted in significant improvement than either one of them alone that merits further clinical investigation.

Background: Bronchial asthma is an inflammatory lung disease characterized by hyper-responsiveness and bronchoconstriction. Beta2 agonists are bronchodilator drugs that possess anti-inflammatory properties. Aim: The present study aimed to investigate the anti-inflammatory and anti-oxidant effects of short-acting (salbutamol) and long-acting(bambuterol) as beta 2 agonists combination. Also, the effect of these drugs, singly and in combination with prednisolone was measured in asthma-induced rats in both lung tissue and broncho-alveolar lavage. Materials and Methods:Wistar rats were sensitized with intraperitoneal (I.P) administration of ovalbumin/Al(OH)3, twenty days later, animals were treated orally with salbutamol 2mg/kg or bambuterol 10 mg/kg or prednisolone 3mg/kg or a combination. Results: Ovalbumin/Al(OH)3-sensitized rats showed a significant elevation in inflammatory mediators (IL-4, MIP1α, PGE2, TNFα) and other oxidative parameters such as MDA, NO in both lung tissue and bronchial alveolar lavage (BAL). Moreover, salbutamol and bambuterol decreased inflammatory mediators and alleviated oxidative stress. These inhibitory effects were greatest when both short and long-acting β2 agonists were used in combination. Also, co-administration of β2 agonists with prednisolone revealed pronounced decreases in all parameters compared to β2 agonists alone. Conclusion: The combined therapy of salbutamol and bambuterol has an anti-inflammatory and anti-oxidant effect on the experimentally induced asthma in both BAL fluids and lung tissues. Also, these drugs in combination with prednisolone possess greater inhibitory effects on inflammatory mediators.

Background and Purpose: Cancer resistance to chemotherapy is a clinical dilemma that eventually leads to increased mortality. It is widely accepted that cancer stem cells (CSCs) have a pivotal role in the development of resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown a promise to combat CSCs, thus, we addressed for the first time the effect of indomethacin on cisplatin (CDDP)-resistant murine breast cancer along with the relevant mechanisms. Experimental Approach: The murine mammary adenocarcinoma, Ehrlich ascites carcinoma (EAC) cells, were made resistant by exposure to CDDP and the surviving cells were then analyzed by flow cytometry for the breast CSCs markers (CD44+CD24-). CDDP heavily enriched the CSCs population which was subsequently injected into mice. After induction of tumors, mice were treated with CDDP, or indomethacin, or co-treatment with both drugs, or left untreated. Upon termination of the treatment period, blood samples were collected to measure the percentage of CSCs markers (CD44, CD24, SCa-1) and the immune cells (CD4+, CD62L+, and CD117+). The tumors were excised and analyzed for the relative expression of drug resistance-mediating miRNAs (miR-7, miR-21, miR-22, and miR-145) in addition to histopathological examination. Key Results: Indomethacin drastically diminished the tumorigenicity of CDDP-resistant cells along with enhancing its sensitivity to CDDP which were correlated with its suppressing ability of CD44+CD24- cells and manipulating effect on miRNAs expression. Besides, indomethacin expanded the pool of immune cells that impart antitumor response. Conclusion and Implications: Indomethacin through targeting CSCs may confer better outcome than conventional chemotherapeutics in the treatment of resistant breast cancer.

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is multifactorial, and the exact underlying mechanisms remain poorly understood. This study aims to investigate the effect of mesalazine and atorvastatin combination in enhancing anti-inflammatory effects and attenuates progression of oxazolone colitis in rats. In the present study, male albino rats (N = 60) were divided into six groups (10 rats each), the first two groups served as normal control and a control saline group. Colitis was induced by intra-rectal administration of oxazolone in the 5th and 7th days after pre-sensitization. Then, rats were divided into untreated group, groups treated with mesalazine or atorvastatin or their combination. Colitis was assessed by colon length, body weight, and incidence of diarrhea, rectal bleeding, and histopathology of colon tissue. Colon tissues were used for measuring interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-13, signal transducer and activator of transcription-3 (STAT-3), myeloperoxidase activity (MPO), reduced glutathione(GSH), and tissue expression of IL-10, tight junction protein zonula occludens (ZO-1), and caspase-3 genes. The combination therapy significantly attenuated progression of UC by decreasing incidence of diarrhea, rectal bleeding, weight loss, IL-13, IL-6, TNF-α, STAT-3, caspase-3, and MPO activity and significantly increased IL-10, ZO-1, colon length, and GSH content, and these effects were more superior to single drugs. These findings showed that combination therapy was able to ameliorate progression of UC and enhance anti-inflammatory effects possibly by restoring IL-10 and ZO-1 levels and limiting IL-6/STAT-3 trans-signaling.

Background: Melasma is an acquired symmetrical hyper-pigmentation that typically presents on the face. Its etiology is multifactorial; its treatment remains a challenge and unsat-isfactory. Glutathione is a major antioxidant which plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis.Aim of the Work: To assess the efficacy and safety of topical and oral glutathione in the treatment of melasma.Patients and Methods: This study included 30 female patients with melasma were selected among those attending the Outpatient Clinic of Dermatology and Venereology De-partment, Tanta University Hospitals during the period between December, 2015 and February, 2017. The studied patients were divided into 3 groups. Group I (10 patients) applied glutathione (2%) cream to right side of the face while placebo cream to left side (as a control) twice daily for 10 weeks. Group II (10 patients) received oral glutathione capsules (500mg/day) for 4 weeks. Group III (10 patients) received oral placebo capsules (as a control) once daily for 4 weeks. Modified melasma area and severity index (MASI) score was calculated before and after therapy. The patients were followed up for a period of 3 months.Results: Significant reduction in modified MASI was observed in patients treated with topical and oral glutathione (p=0.011) and (p=0.007) respectively, while patients treated with topical or oral placebo had no response. Topical and oral forms of glutathione were safe and well tolerated.Conclusion: Glutathione is safe, tolerable and effective whitening agent when used in topical cream (2%) and also in oral form in treatment of melasma.

Liver fibrosis is the consequence of hepatocyte injury that leads to the activation of hepatic stellate cells (HSC). The treatment of choice is Liver transplantation; however, it has many problems such as surgery-related complications, immunological rejection and high costs associated with the procedure. Stem cell-based therapy would be a potential alternative, so the aim of this study is to investigate the therapeutic potential of human umbilical cord mononuclear cells (MNC) and mouse bone marrow cells (BMC) against carbon tetrachloride (CCl4) induced liver fibrosis in mice and compare it with that of silymarin. In the present study, male albino mice (N=60) were divided into six groups (10 mice each), the first group served as the normal control group while the remaining five groups were rendered fibrotic by intraperitoneal injections of CCl4 and being left for 6 weeks to develop hepatic fibrosis. Thereafter, the mice were divided into CCl4 group, CCl4 group receiving MNC or BMC or silymarin or MNC and silymarin combination. After the specified treatment period, animals were then euthanized, blood and tissue samples were collected for measurement of alanine aminotransferase(ALT), aspartate aminotransferase(AST), malondialdehyde(MDA), reduced glutathione(GSH), collagen, Laminin, transforming growth factor β1(TGFβ1), tumor necrosis factor alpha(TNFα). MNC, BMC, and the combination therapy showed a significant decrease in ALT, AST, MDA, collagen, Laminin, TGFβ1, and TNFα and a significant increase in GSH. The data displayed a similar regression of fibrosis with the histological and immunohistological parameters. In conclusion, MNC, BMC and the combination therapy showed a potential therapeutic effect against liver fibrosis via reducing oxidative stress, inflammatory mediators, and fibrogenic markers.

Ulcerative colitis is a chronic auto-inflammatory disorder confined to the colorectal region. It is challenging to find an absolute treatment and current therapy aims to ameliorate symptoms, decrease relapses and prevent prognosis of colorectal cancer. In the present study, we investigated the possible action of xanthine oxidase inhibitors in murine colitis model by measuring different indicative parameters and comparing the results to those of the reference sulfasalazine. Also, we compared the effects of combining sulfasalazine and allopurinol to each drug alone. Dextran Sodium Sulfate (DSS) is used in this study to induce ulcerative colitis in male wistar rats as it is known to be the closest model that mimics human ulcerative colitis. Allopurinol was given prior to colitis induction by four days and febuxostat for six days before induction with DSS (5% w/v) and continue to give them concomitantly during the induction.Il-1β, malondialdehyde, reduced glutathione (GSH), xanthine oxidase, and superoxide dismutase were measured in colonic tissue. We also measured concentrations of IL-1β, Il-6 and uric acid in serum. Allopurinol dose-dependently ameliorated biochemical injuries. Febuxostat has shown better results than allopurinol and sulfasalazine, and this is the first study to demonstrate this.

The current study investigated the combinatorial effect of pravastatin (PRAV) and bone marrow mononuclear cells (BM-MNC) on acute myocardial infarction (AMI) induced experimentally in rats. After induction of MI, rats were given oral PRAV (20 mg/kg/day) for 28 days or a bolus intravenous injection (via lateral vein) of a total of 14 × 10(6) autologous BM-MNC or a combination of both. Serum brain natriuretic peptide (BNP) and histologic changes in cardiac tissues were assessed. Cardiac contents of lipid peroxides, superoxide dismutase (SOD) and inflammatory biomarkers including tumor necrosis factor (TNF)-α and interleukin (IL)-1β as well as vascular endothelial growth factor (VEGF) and nitric oxide (NO) were also measured. Combined PRAV and BM-MNC treatment significantly suppressed serum BNP. Cardiac cell apoptosis and inflammatory cell infiltration in heart tissue decreased significantly in both the PRAV and the PRAV + BM-MNC groups. Cardiac lipid peroxides along with TNFα and IL-1β levels were significantly reduced in both the PRAV and PRAV + BM-MNC hosts with an increase in SOD levels. However, the combined treatment increased cardiac NO levels and did not modify cardiac VEGF levels. The current results indicated that administration of BM-MNC improved the therapeutic efficacy of PRAV treatment by improving the morphology of infarcted hearts as well as decreasing inflammation in a host, but did not do so by inducing therapeutic angiogenesis.

There is growing interest in re-evaluation of older antibiotics with the wide spread of pathogen resistance, especially gram negative bacteria, which impair treatment of some infections. In contrast various studies have reported that some antibiotics have efficacy in clearing resistant bacterial infections. On account of that it was interesting to evaluate the efficacy of erythromycin, chloramphenicol and/or tenoxicam in curing and/or relieving wound infection of highly resistant Escherichia coli and investigate the possible mechanisms beyond their antibacterial activity. This was achieved through evaluating highly resistant E. coli strains in vitro using agar dilution and in vivo rat models of E. coli infected wound and acute inflammation by carrageenin, where possible mechanisms were evaluated through measuring immunological mediators and histopathological examination. This study revealed that in vivo, erythromycin alone or in combination with tenoxicam significantly improved the healing of infected skin wounds with E. coli irresspective of resistancy in vitro. In addition to the improvement of immunological mediators involved in inflammatory reaction, oxidative stress and in cytokines expression as response to the bacterial infection in vivo. On the other hand chloramphenicol neither alone nor in combination with tenoxicam, achieved any significant effect. Tenoxicam didn’t show antimicrobial activity alone nor in combination with tested antibiotics in vitro, but it has shown synergestic activity in combination with tested antibiotics in vivo. Thus we concluded that immunomodulatory activity of erythromycin through anti-inflammatory and antioxidant effects was the possible mechanisms by which this antibiotic had healed infection with resistant E. coli in vivo, despite its resistancy to this antibiotic in vitro.

Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho- or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3- and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr)4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the world. Several signaling pathways are involved in the pathogenesis of DN including elevation in level of angiotensin II, formation of advanced glycation end products (AGE), activation of protein kinase c (PKC), and lipid accumulation. These pathways activate one another mutually leading to oxidative stress, increasing expression of transforming growth factor beta-1(TGF-β 1) and release of interleukins and adhesion molecules, so the aim of this study is to interrupt more than pathogenic pathway to ameliorate the progression of DN. In the present study, white male rats (N=48) were divided into six groups (8 rats each), the first two groups served as normal control and a control vehicle group while the remaining four groups were rendered diabetic by a single intraperitoneal injection of Streptozotocin (STZ) and being left for 4 weeks to develop DN. Thereafter, the rats were divided into DN group, DN group receiving Telmisartan or Sildenafil or Telmisartan Sildenafil combination. After the specified treatment period, urine samples were collected (using metabolic cages) to measure proteinuria, animals were then euthanized, blood and tissue samples were collected for measurement of Blood glucose,BUN, S.Cr, LDL, NO, TGF-β1, IL-1β, AGEPs, and SOD. The combination therapy showed significant decrease in BUN, S.Cr,LDL, TGF-β1, IL-1β, Proteinuria and AGEPs and significant increase in SOD and NO. The findings showed that combination therapy was able to ameliorate DN and that the effects were superior to the single drugs alone.

SummaryBackground There are numerous methods currently available for the management of xanthelasma. These include surgical excision, laser ablation using a variety of lasers and chemical cauterization. However, each method of treatment is associated with particular limitations and side effects. Objectives To assess the clinical efficacy and tolerability of different concentrations of topical trichloroacetic acid (TCA) vs. carbon dioxide laser in the treatment of patients with xanthelasma palpebrarum. Methods Thirty patients with xanthelasma palpebrarum were classified into four groups, treated by TCA 35%, 50%, 70%, and CO2 laser, respectively. Lipid profile was estimated for all patients. Results Both TCA peeling 70% and carbon dioxide laser ablation showed more significant clinical efficacy and tolerability with least number of sessions in the treatment of xanthelasma palpebrarum than 50% and 35% TCA peeling. Post-therapy erythema and hypopigmentation were more with TCA 70%. Post-therapy hyperpigmentation was more with TCA (50%). There was a significant improvement in patients with normal lipid profile than those with abnormal profile. Conclusion Both TCA peeling 70% and carbon dioxide laser ablation are highly effective and well tolerated with least number of sessions in the treatment of xanthelasma palpebrarum.

Histamine, involved in many inflammatory reactions and immune responses, is reported to suppress--via H4R stimulation--injury concomitant with the late phase of warm hepatic ischemia/re-perfusion (I/R). The current study investigated the possible effects of histamine on the acute phase of hepatic I/R injury, and the possible underlying mechanisms like oxidative stress and release of inflammatory cytokines (e.g., tumor necrosis factor (TNF)-α nd interleukin [IL]-12). Rats were divided into naive, sham-operated, and I/R groups. The I/R group was divided into sub-groups and pre-treated with histaminergic ligands before induction of ischemia. Anesthetized rats were subjected to warm ischemia for 30 min by occlusion of the portal vein and hepatic artery, then re-perfused for 90 min. Rats in the control I/R group showed significant increases in hepatic malondialdehyde (MDA), TNFα, and IL-12 contents, and in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, along with significant decreases in hepatic reduced glutathione (GSH) content and marked diffuse histopathologic damage. Pre-treatment with histamine resulted in significant mitigation of each of these end-points. The protective effect of histamine was not antagonized by pre-treatment with mepyramine (H1R antagonist) or ranitidine (H2R antagonist) and completely reversed by pre-treatment with thioperamide (H3R and H4R antagonist). In addition, the histamine protective effect was mimicked by pre-treatment of rats with clozapine (H4R agonist). These observations strongly suggested that histamine has a protective effect against hepatic I/R-mediated tissue injury during the acute phase, and this effect was mediated through an H4R stimulation that led to a decrease in IL-12 and TNFα production--outcomes that consequently decreased localized oxidative stress and afforded hepatic protection in general.