Chemotherapeutic potential of betanin/capecitabine combination targeting colon cancer: experimental and bioinformatic studies exploring NFκB and cyclin D1 interplay.

Introduction: Betanin (C24H26N2O13) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approach was designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-α (4.58-fold), NFκB (5.33-fold), IL-1ß (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) and immunostaining for NFκB (2.94-fold) were high while periodic-acid Schiff staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients.

Leflunomide-induced cardiac injury in adult male mice and bioinformatic approach identifying Nrf2/NF-κb signaling interplay.

Leflunomide (LFND) is an immunosuppressive and immunomodulatory disease-modifying antirheumatic drug (DMARD) that was approved for treating rheumatoid arthritis. LFND-induced cardiotoxicity was not fully investigated since its approval. We investigated the cardiac injury in male mice and identified the role of nuclear factor erythroid 2-related factor 2/nuclear factor-κ B (Nrf2/NF-κB) signaling. Male albino mice were assigned into five groups as control, vehicle, and LFND (2.5, 5, and 10 mg/kg). We investigated cardiac enzymes, histopathology, and the mRNA expression of Nrf2, NF-κB, BAX, and tumor necrosis factor-α (TNF-α). The bioinformatic study identified the interaction between LFND and Nrf2/NF-κB signaling; this was confirmed by amelioration in mRNA expression (0.5- to 0.34-fold decrease in Nrf2 and 2.6- to 4.61-fold increases in NF-κB genes) and increased (1.76- and 2.625-fold) serum creatine kinase (CK) and 1.38- and 2.33-fold increases in creatine kinase-MB (CK-MB). Histopathological results confirmed the dose-dependent effects of LFND on cardiac muscle structure in the form of cytoplasmic, nuclear, and vascular changes in addition to increased collagen deposits and apoptosis which were increased compared to controls especially with LFND 10 mg/kg. The current study elicits the dose-dependent cardiac injury induced by LFND administration and highlights, for the first time, dysregulation in Nrf2/NF-κB signaling.

Antitumor activity and targeting p53-PUMA mRNA expression by 5-flurouracil PLGA-lipid polymeric nanoparticles in mouse mammary carcinomas: comparison to free 5-flurouracil.

Polymeric poly (lactic-co-glycolic acid) (PLGA)-lipid hybrid nanoparticles (PNPs)-based therapy are powerful carriers for various therapeutic agents. This study was conducted to evaluate the chemotherapeutic potential of free 5-flurouracil (5FU) and synthetized 5FU-PNPs and impact on p53-dependent apoptosis in mammary carcinomas (MCs) grown in mice. Breast cancer cells were injected in Swiss albino female mice and 2 bilateral masses of MC were confirmed after one week. Mice were distributed to five experimental groups; Group 1: MC control group. Groups 2 and 3: MC + free 5FU [5 or 10 mg per kg] groups. Groups 4 and 5: synthetized MC+ 5FU-PNPs [5 or 10 mg per kg] groups. Medications were administered orally, twice weekly for 3 weeks. Then, tumors were dissected, and sections were stained with hematoxylin-eosin (HE) while the other MC was used for measuring of cell death and inflammatory markers. Treatment with 5FU-PNPs suppressed the MC masses and pathologic scores based on HE-staining. Similarly, greater proapoptotic activity was recorded in 5FU-PNPs groups compared to free 5FU groups as shown by significant upregulation in tumoral p53 immunostaining. The current results encourage the utility of PNPs for improving the antitumor effect of 5FU. The chemotherapeutic potential was mediated through enhancement of tumoral p53-mediated p53 up-regulated modulator of apoptosis (PUMA) genes. Additional studies are warranted for testing the antitumor activity of this preparation in other mouse models of breast cancer.

Marula oil nanoemulsion improves motor function in experimental parkinsonism via mitigation of inflammation and oxidative stress.

Introduction: Parkinson's disease (PD) is a neurologic condition exhibiting motor dysfunction that affects old people. Marula oil (M-Oil) has been used longley in cosmetics and curing skin disorders. M-Oil is particularly stable due to its high concentration of monounsaturated fatty acids and natural antioxidants. The current study formulated M-Oil in an o/w nanoemulsion (M-NE) preparations and tested its anti-inflammatory and antioxidant actions against experimental parkinsonism. Methods: Four experimental groups of male albino mice were used and assigned as vehicle, PD, PD + M-Oil and PD + M-NE. Locomotor function was evaluated using the open field test and the cylinder test. Striatal samples were used to measure inflammatory and oxidative stress markers. Results: The results indicated poor motor performance of the mice in PD control group then, improvements were recorded after treatment with crude M-Oil or M-NE. In addition, we found high expression and protein of inflammatory markers and malondialdehyde levels in PD group which were downregulated by using doses of crude M-Oil or M-NE. Hence, formulating M-Oil in form of M-NE enhanced its physical characters. Discussion: This finding was supported by enhanced biological activity of M-NE as anti-inflammatory and antioxidant agent that resulted in downregulation of the inflammatory burden and alleviation of locomotor dysfunction in experimental PD in mice.

α-Hederin Saponin Augments the Chemopreventive Effect of Cisplatin against Ehrlich Tumors and Bioinformatic Approach Identifying the Role of SDF1/CXCR4/p-AKT-1/NFκB Signaling.

Stromal cell-derived factor-1 (SDF1) and its C-X-C chemokine receptor type 4 receptor (CXCR4) are significant mediators for cancer cells' proliferation, and we studied their expression in Ehrlich solid tumors (ESTs) grown in mice. α-Hederin is a pentacyclic triterpenoid saponin found in Hedera or Nigella species with biological activity that involves suppression of growth of breast cancer cell lines. The aim of this study was to explore the chemopreventive activity of α-hederin with/without cisplatin; this was achieved by measuring the reduction in tumor masses and the downregulation in SDF1/CXCR4/pAKT signaling proteins and nuclear factor kappa B (NFκB). Ehrlich carcinoma cells were injected in four groups of Swiss albino female mice (Group1: EST control group, Group2: EST + α-hederin group, Group3: EST + cisplatin group, and Group4: EST+α-hederin/cisplatin treated group). Tumors were dissected and weighed, one EST was processed for histopathological staining with hematoxylin and eosin (HE), and the second MC was frozen and processed for estimation of signaling proteins. Computational analysis for these target proteins interactions showed direct-ordered interactions. The dissected solid tumors revealed decreases in tumor masses (~21%) and diminished viable tumor regions with significant necrotic surrounds, particularly with the combination regimens. Immunohistochemistry showed reductions (~50%) in intratumoral NFκß in the mouse group that received the combination therapy. The combination treatment lowered the SDF1/CXCR4/p-AKT proteins in ESTs compared to the control. In conclusion, α-hederin augmented the chemotherapeutic potential of cisplatin against ESTs; this effect was at least partly mediated through suppressing the chemokine SDF1/CXCR4/p-AKT/NFκB signaling. Further studies are recommended to verify the chemotherapeutic potential of α-hederin in other breast cancer models.

Metformin suppresses LRG1 and TGFß1/ALK1-induced angiogenesis and protects against ultrastructural changes in rat diabetic nephropathy.

Diabetic nephropathy (DN) has high prevalence and poor prognosis which make it a research priority for scientists. Since metformin, a hypoglycaemic drug, has been found to prolong the survival of mice with DN. This study aims at investigating the molecular mechanisms leading to DN in rats and to explore the role of leucine-rich α-2-glycoprotein-1 (LRG1), activin-like kinase1 (ALK1), and transforming growth factor-ß (TGFß1) in the pathologic alterations seen in DN. The aim was also extended to explore the protective action of metformin against DN in rats and its influence on LRG1and ALK1/TGFß1 induced renal angiogenesis. 24 male rats were used. Rats were assigned as, the vehicle group, the diabetic control group and diabetic + metformin (100 and 200 mg/kg) groups. Kidney samples were processed for histopathology, immunohistochemistry and biochemical analysis. Bioinformatic analysis of studied proteins was done to determine protein-protein interactions. Metformin reduced serum urea and creatinine significantly, decreased the inflammatory cytokine levels and reduced LRG1, TGFß1, ALK1 and vascular endothelial growth factor (VEGF) proteins in rat kidneys. Bioinformatic analysis revealed interactions between the studied proteins. Metformin alleviated the histopathological changes observed in the diabetic rats such as the glomerular surface area and increased Bowman's space diameter. Metformin groups showed decreased VEGF immunostaining compared to diabetic group. Metformin shows promising renoprotective effects in diabetic model that was at least partly mediated by downregulation of LRG1 and TGFß1/ALK1-induced renal angiogenesis. These results further explain the molecular mechanism of metformin in DN management.

Hesperetin mitigates sorafenib-induced cardiotoxicity in mice through inhibition of the TLR4/NLRP3 signaling pathway.

Sorafenib is an oral multi-kinase receptor inhibitor that targets various signaling pathways. It is used as the first line of treatment in advanced hepatocellular and renal cell carcinomas. Sorafenib was reported to induce cardiotoxicity due to myocyte necrosis. Hesperetin is a naturally occurring flavonoid with antioxidant and anti-inflammatory capabilities. This study investigated the putative protective effect of hesperetin against sorafenib-induced cardiotoxicity in mice through downregulation of NLRP3/TLR4 signaling and inhibition of apoptosis. Twenty-four male Swiss mice were distributed into four groups: untreated control, hesperetin (50 mg/kg/day, orally), sorafenib (100 mg/kg/day, orally), and combination (Hesperetin+Sorafenib). After a three-week treatment period, various biochemical parameters in cardiac tissues were assessed. TNF-α, IL-1ß, and IL-6 levels were measured. Moreover, TLR4 and NLRP3 expressions were evaluated using Western blot analysis. Histopathological examination and immunohistochemical assessment of apoptotic activity were done. Compared with the sorafenib group, the combination group exhibited reduced TNF-α, IL-1ß, IL-6 levels and lower NLRP3/TLR4 expressions. Histologically, the combination group showed improved myocardial histology and a marked decrease in collagen deposition. Immunohistochemical examination showed decreased caspase-3 and increased Bcl-2 expression. Before recommending hesperetin as an adjuvant, clinical studies are warranted for mitigating sorafenib cardiotoxicity.

Formulation and Characterization of O/W Nanoemulsions of Hemp Seed Oil for Protection from Steatohepatitis: Analysis of Hepatic Free Fatty Acids and Oxidation Markers.

Non-alcoholic steatohepatitis (NASH) is a common type of metabolic liver disease which is characterized by fatty changes associated with hepatocyte injury, lobular inflammation, and/or liver fibrosis. Nanoemulsions are kinetically stable colloidal systems characterized by small droplet size. Hemp seed oil is a natural oil derived from Cannabis sativa seeds. The current study was designed to formulate nanoemulsion preparations of hemp seed oil with promising enhanced biological activity against high fat (HF) diet induced NASH in rats. Four nanoemulsion formulas (NEFs) were formulated based on high-pressure homogenization technique and evaluated for droplet size, zeta potential (ZP), polydispersity index (PDI), electrical conductivity, pH, and viscosity, as well as the preparation stability. The best NEF was selected to perform an in vivo rat study; selection was based on the smallest droplet size and highest physical stability. Results showed that NEF#4 showed the best physiochemical characters among the other preparations. Twenty male rats were assigned to four groups as follows: normal, NASH control, NASH + hemp seed oil and NASH + hemp seed oil NEF4. The rats were tested for body weight (BWt) change, insulin resistance (IR) and hepatic pathology. The hemp seed NEF#4 protected against NASH progression in rats and decreased the % of BWt gain compared to the original Hemp seed oil. NEF#4 of Hemp seed oil showed greater protective activity against experimental NASH and IR in rats. Hence, we can consider the nanoemulsion preparations as a useful tool for enhancing the biological action of the hemp seed oil, and further studies are warranted for application of this technique for preparing natural oils aiming at enhancing their activities.

Formulation and Characterization of Metformin-Loaded Ethosomes for Topical Application to Experimentally Induced Skin Cancer in Mice.

To achieve the best treatment of skin cancer, drug penetration inside the deepest layers of the skin is an important scientific interest. We designed an ethosome formulation that serves as a carrier for metformin and measured the in vitro skin permeation. We also aimed to measure the antitumor activity of the optimal ethosomal preparation when applied topically to chemically induced skin cancer in mice. We utilized a statistical Box-Behnken experimental design and applied three variables at three levels: lecithin concentration, cholesterol concentration and a mixture of ethanol and isopropyl alcohol concentrations. All formulations were prepared to calculate the entrapment efficiency %, zeta potential, size of the vesicles and drug release % after 1, 2, 4, 8 and 24 h. The size of the vesicles for the formulations was between 124 ± 14.2 nm and 560 ± 127 nm, while the entrapment efficiency was between 97.8 ± 0.23% and 99.4 ± 0.24%, and the drug release % after 8 h was between 38 ± 0.82% and 66 ± 0.52%. All formulations were introduced into the Box-Behnken software, which selected three formulations; then, one was assigned as an optimal formula. The in vivo antitumor activity of metformin-loaded ethosomal gel on skin cancer was greater than the antitumor activity of the gel preparation containing free metformin. Lower lecithin, high ethanol and isopropyl alcohol and moderate cholesterol contents improved the permeation rate. Overall, we can conclude that metformin-loaded ethosomes are a promising remedy for treating skin cancers, and more studies are warranted to approve this activity in other animal models of skin cancers.

Celastrol and thymoquinone alleviate aluminum chloride-induced neurotoxicity: Behavioral psychomotor performance, neurotransmitter level, oxidative-inflammatory markers, and BDNF expression in rat brain.

Exposure to aluminum chloride (AlCl3) induces progressive multiregional neurodegeneration in animal models by promoting oxidative stress and neuroinflammation. The current study was designed to assess the potential efficacy of the natural antioxidants celastrol and thymoquinone (TQ) for alleviating AlCl3-induced psychomotor abnormalities and oxidative-inflammatory burden in male albino rats. Four treatment groups were compared: (i) a vehicle control group, (ii) a AlCL3 group receiving daily intraperitoneal (i.p.) injection of AlCl3 (10 mg/kg) for 6 weeks, (iii) a AlCl3 plus TQ (10 mg/kg, i.p.) cotreatment group, and (iv) a AlCl3 plus celastrol (1 mg/kg, i.p.) cotreatment group. Open-field, rotarod, and forced swimming tests were conducted to assess locomotor activity, motor coordination, anxiety-like behavior, and depressive-like behavior. Acetylcholine (ACh), dopamine, and serotonin levels were measured in brain homogenates. Malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity were measured as oxidative stress markers, while tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6) expression levels were measured as inflammatory markers. Brain derived neurotrophic factor (BDNF) mRNA was measured as an index for the endogenous neuroprotective response. Daily AlCl3 injection reduced free ambulation, impaired motor coordination, promoted anxiety- and depression-like behaviors, reduced whole-brain ACh, dopamine, and serotonin concentrations, increased MDA accumulation, reduced TAC, elevated TNF-α and IL-6, and suppressed BDNF mRNA expression. All of these effects were significantly reversed by TQ or celastrol cotreatment. Thus, TQ and celastrol may be promising treatments for AlCl3-induced neurotoxicity as well as neurodegenerative diseases involving oxidative stress and neuroinflammation.

Formulation and Characterization of Doxycycline-Loaded Polymeric Nanoparticles for Testing Antitumor/Antiangiogenic Action in Experimental Colon Cancer in Mice.

Nanotherapeutics can enhance the characteristics of drugs, such as rapid systemic clearance and systemic toxicities. Polymeric nanoparticles (PRNPs) depend on dispersion of a drug in an amorphous state in a polymer matrix. PRNPs are capable of delivering drugs and improving their safety. The primary goal of this study is to formulate doxycycline-loaded PRNPs by applying the nanoprecipitation method. Eudragit S100 (ES100) (for DOX-PRNP1) and hydroxypropyl methyl cellulose phthalate HP55 (for DOX-PRNP2) were tested as the drug carrying polymers and the DOX-PRNP2 showed better characteristics and drug release % and was hence selected to be tested in the biological study. Six different experimental groups were formed from sixty male albino mice. 1,2,-Dimethylhydrazine was used for 16 weeks to induce experimental colon cancer. We compared the oral administration of DOX-PRNP2 in doses of 5 and 10 mg/kg with the free drug. Results indicated that DOX-PRNP2 had greater antitumor activity, as evidenced by an improved histopathological picture for colon specimens as well as a decrease in the tumor scores. In addition, when compared to free DOX, the DOX-PRNP2 reduced the angiogenic indicators VEGD and CD31 to a greater extent. Collectively, the findings demonstrated that formulating DOX in PRNPs was useful in enhancing antitumor activity and can be used in other models of cancers to verify their efficacy and compatibility with our study.

Nifuroxazide Mitigates Angiogenesis in Ehlrich's Solid Carcinoma: Molecular Docking, Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling.

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich's mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich's solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-ß, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.

Antitumor Activity of Nitazoxanide against Colon Cancers: Molecular Docking and Experimental Studies Based on Wnt/ß-Catenin Signaling Inhibition.

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.

Leflunomide Induces Dose-Dependent Lung Injury in Mice via Stimulating Vimentin and NLRP3 Inflammasome Production.

Recently, the therapeutic importance of the anti-rheumatic drug, leflunomide, has been increased after the involvement of leflunomide in treating other autoimmune diseases and its promising role in retarding human malignancies. Few studies have focused on the safety in human or animals without clear outlining of the pathologic features on target organs. One clinical study related leflunomide with significant pulmonary complications in predisposed individuals. The current study examined the dose-dependent lung injury produced by leflunomide in healthy mice. Albino mice were allocated into four different groups. Group (1): Vehicle control group, Group (2-4): mice received leflunomide (2.5, 5 or 10 mg/kg), respectively, for 8 weeks and then lungs were dissected from the mice for histopathological examination and fibrosis evaluation (Masson's trichrome staining and α-smooth muscle actin immunohistochemistry). Enzyme linked immunosorbent assay was used to assess the vimentin and other inflammatory factors in the lung homogenate whereas Western blot analysis was employed to assess α-smooth muscle actin, vimentin and collagen 1. Results indicated that leflunomide induced dose-dependent pulmonary injury and the high dose and increased the vimentin, inflammatory markers (NLRP3 and interlukin-1ß). Histologic examination showed distorted architecture, marked inflammatory cells infiltrate and increase collagen content. The findings were supported by Western blotting and the immunohistochemical study which showed greater pulmonary α-smooth muscle actin and vimentin content. In conclusion, the current results highlighted that leflunomide produced dose-dependent pulmonary toxicities that requires further investigation of the nature of injury.

Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis.

Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor-k B (NF-kB) inflammatory axis. Diabetes was prompted by an alloxan injection (180 mg/kg) to albino mice. On the ninth week after diabetes induction, DNP was confirmed. Diabetic mice were randomly allocated to two groups (six mice each); a diabetes mellitus (DM) group and DM+memantine group (10 mg/kg, daily) for five weeks. DNP-related behaviors were assessed in terms of thermal hyperalgesia and mechanical allodynia by hot-plate and von Frey filaments. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the spinal glutamate, interleukin-1 beta (IL-1ß), and tumor necrosis factor-α (TNF-α). The spinal levels of N-methyl-D-aspartate type 1 receptor (NMDAR1), HMGB1, TLR4, and phosphorylated NF-kB were assessed using Western blotting. Histopathological investigation of the spinal cord and sciatic nerves, together with the spinal cord ultrastructure, was employed for assessment of the neuroprotective effect. Memantine alleviated pain indicators in diabetic mice and suppressed excessive NMDAR1 activation, glutamate, and pro-inflammatory cytokine release in the spinal cord. The current study validated the ability of memantine to combat the HMGB1/TLR4/NF-kB axis and modulate overactive glutamate spinal transmission, corroborating memantine as an appealing therapeutic target in DNP.

Preoperative Diagnosis Failure for a Rare Gastric Collision Tumor: A Case Report.

Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract (GIT), usually occur as a solitary neoplasm. Inflammatory florid polyp (IFP) is a solitary rare benign lesion of the gastrointestinal tract, mainly occur in the gastric antrum, whose atypical presentation can mimic GISTs or other malignant tumors, therefore the synchronous occurrence of GISTs and IFP is extremely rare. We had a case of a 58-year-old man that was presented with recurrent epigastric pain and recurrent melena. Upper endoscopic examination revealed a large polypoid antrum polyp measured 7 cm at greatest dimension with focal ulceration. Clinical and radiological features did not reach the definite diagnosis until histopathological evaluation with immunohistochemical analysis was performed. Surgical intervention is recommended and partial gastrectomy was done with wide resection margins. Histological examination revealed two distinct GISTs and IFP parts presenting a collision tumor that showed spindle and epitheloid cells consistent with GISTs with histological features of florid polyp showed a characteristic perivascular onion-skin arrangement of spindle cells with dense chronic inflammatory infiltrate including eosinophils and lymphocytes. Immunohistochemical studies have been done and revealed an association between GISTs and IFP. To the best of our knowledge, this is the first case of a collision tumor consisting of a GIST and an IFP arising in the stomach. In conclusion, the gastrointestinal stromal tumor is the comments mesenchymal tumor of GIT and IFP is a rare benign lesion of GIT therefore association between GIST and IFP as a collision tumor is extremely rare.

Chemopreventive Effect of 5-Flurouracil Polymeric Hybrid PLGA-Lecithin Nanoparticles against Colon Dysplasia Model in Mice and Impact on p53 Apoptosis.

The use of 5-fluorouracil (5FU) is associated with multifaceted challenges and poor pharmacokinetics. Poly(lactic-co-glycolic acid)-lipid hybrid nanoparticles (PLNs)-based therapy has received attention as efficient carriers for a diversity of drugs. This study evaluated the in vivo chemotherapeutic and anti-proliferative efficacy of 5FU-loaded PLNs against 1,2-dimethylhydrazine (Di-MH) prompted colon dysplasia in mice compared to free 5FU. 5FU PLNs were prepared. Male Swiss albino mice were distributed to six experimental groups. Group 1: Saline group. All the other groups were injected weekly with Di-MH [20 mg/kg, s.c.]. Group 2: Di-MH induced colon dysplasia control group. Groups 3 and 4: Di-MH + free 5FU treated group [2.5 and 5 mg/kg]. Groups 5 and 6: Di-MH + 5FU-PLNs treated group [2.5 and 5 mg/kg]. Free 5FU and 5FU-PLNs doses were administered orally, twice weekly. Treatment with 5FU-PLNs induced a higher cytoprotective effect compared to free 5FU as indicated by lower mucosal histopathologic score and reduction in number of Ki-67 immunpositive proliferating nuclei. Additionally, there was significant upregulation of p53 and caspase 3 genes in colon specimens. Our results support the validity of utilizing the PLNs technique to improve the chemopreventive action of 5FU in treating colon cancer.

Chemopreventive effect of α-hederin/carboplatin combination against experimental colon hyperplasia and impact on JNK signaling.

Colon cancer is the commonest cancer worldwide. α-Hederin is a monodesmosidic triterpenoid saponin possessing diverse pharmacological activities. The running experiment was designed to test the chemopreventive activity of α-hederin when used as an adjuvant to carboplatin in an experimental model of mouse colon hyperplasia induced by 1,2-dimethylhydrazine (DMH). Fifty male Swiss albino mice were classified into five groups: group (I): saline group, group (II): DMH-induced colon hyperplasia control group, group (III): DMH + carboplatin (5 mg/kg) group, group (IV): DMH + α-hederin (80 mg/kg) group, and group (V): DMH + carboplatin (5 mg/kg)+α-hederin (80 mg/kg) group. Analyzing of colonic tissue indicated that the disease control group showed higher colon levels of phospho-PI3K to total-PI3K, phospho-AKT to total-AKT and cyclin D1 concurrent with lower phospho-JNK/total JNK ratio and caspase 3. However, treatment with α-hederin, in combination with carboplatin, favorably ameliorated phosphorylation of PI3K/AKT/JNK proteins, increased colon caspase 3 and downregulated cyclin D1. Microscopically, α-hederin, in combination with carboplatin, produced the most reduction in the histologic hyperplasia score, enhanced the goblet cell survival in periodic acid Schiff staining and reduced proliferation (Ki-67 immunostaining) in the current colon hyperplasia model. Collectively, the current study highlighted for the first time that using α-hederin as an adjuvant to carboplatin enhanced its chemopreventive activity, improved JNK signaling and increased apoptosis. Hence, further studies are warranted to test α-hederin as a promising candidate with chemotherapeutic agents in treating colon cancer.

Protective effect of metformin on rat diabetic retinopathy involves suppression of toll-like receptor 4/nuclear factor-k B expression and glutamate excitotoxicity.

Microvascular complications of diabetes mellitus are progressively significant reasons for mortality. Metformin (MET) is considered as the first-line therapy for type 2 diabetes patients, and may be especially beneficial in cases of diabetic retinopathy although the precise mechanisms of MET action are not fully elucidated. The current study was designed to inspect the antioxidant and modulatory actions of MET on DRET in streptozotocin-induced diabetic rats. The effect of MET on the toll-like receptor 4/nuclear factor kappa B (TLR4/NFkB), inflammatory burden and glutamate excitotoxicity was assessed. Twenty-four male rats were assigned to four experimental groups: (1) Vehicle group, (2) Diabetic control: developed diabetes by injection of streptozotocin (60 mg/kg, i.p.). (3&4) Diabetic + MET group: diabetic rats were left for 9 weeks without treatment and then received oral MET 100 and 200 mg/kg for 6 weeks. Retinal samples were utilized in biochemical, histological, immunohistochemical and electron microscopic studies. MET administration significantly decreased retinal level of insulin growth factor and significantly suppressed the diabetic induced increase of malondialdehyde, glutamate, tumor necrosis factor-α and vascular endothelial growth factor (VEGF). Further, MET decreased the retinal mRNA expression of NFkB, tumor necrosis factor-α and TLR4 in diabetic rats. The current findings shed the light on MET's efficacy as an adjuvant therapy to hinder the development of diabetic retinopathy, at least partly, via inhibition of oxidative stress-induced NFkB/TLR4 pathway and suppression of glutamate excitotoxicity.

Retinoprotective effect of donepezil in diabetic mice involves mitigation of excitotoxicity and activation of PI3K/mTOR/BCl2 pathway.

Donepezil (DNPZ) has shown neuroprotective effect in many disorders. The current study tested the putative retinoprotection provided by donepezil in mouse diabetic retinopathy. Swiss albino mice were allocated to, 1] saline control, 2] diabetic, 3&4] diabetic+DNPZ (1 or 4 mg/kg). After induction of diabetes, mice were maintained for 8 weeks then DNPZ therapy was launched for 28 days. Retinas were isolated and used for histopathology and immunohistochemistry for caspase 3 and the anti-apoptotic protein, B-cell lymphoma 2 (BCl2). Retinas were examined for glutamate, acetylcholine and oxidation markers. Western blot analysis measured inflammatory cytokines, N-methyl-d-aspartate receptors (NMDARs), phosphorylated and total phosphatidylinositol-3 kinase and mTOR, BCl2 and cleaved caspase 3. Significant histopathological changes and decreased thickness were found in diabetic retinas (125.52 ± 2.85 vs. 157.15 ± 7.55 in the saline group). In addition, retinal glutamate (2.39-fold), inflammatory cytokines and NMDARs proteins (4.9-fold) were higher in the diabetic retinas. Western blot analysis revealed low ratio of phosphorylated/total PI3K (0.21 ± 0.043 vs. 1 ± 0.005) and mTOR (0.18 ± 0.04 vs. 1 ± 0.005), low BCl2 (0.28 ± 0.06 vs. 1 ± 0.005) and upregulated cleaved caspase 3 (5.18 ± 1.27 vs. 1 ± 0.05 in the saline group) versus the saline control. DNPZ ameliorated the histopathologic manifestations and to prevent the decrease in retinal thickness. DNPZ (4 mg/kg) improved phosphorylation of PI3K (0.76 ± 0.12 vs. 0.21 ± 0.04) and mTOR (0.59 ± 0.09 vs. 0.18 ± 0.04) and increased BCl2 (0.75 ± 0.08 vs. 0.28 ± 0.06) versus the diabetic control group. This study explained the retinoprotective effect of DNPZ in mouse diabetic retinopathy and highlighted that mitigation of excitotoxicity, improving phosphorylation of PI3K/mTOR and increasing BCl2 contribute to this effect.