Luteolin/ZnO nanoparticles attenuate neuroinflammation associated with diabetes via regulating MicroRNA-124 by targeting C/EBPA.

OBJECTIVE: The most prevalent brain-specific microRNA, MicroRNA-124, exhibits anti-inflammatory properties. Luteolin nano-formulation with Zn oxide in the form of L/ZnO NPs may boost anti-diabetic properties; however, its beneficial effect on miRNAs is yet unknown in diabetes. The effectiveness of L/ZnONPs supplements in preventing diabetic neurodegeneration by modulating inflammatory responses in a diabetic model was investigated. METHODS: A diabetic rat model was induced by a high-fat diet and streptozotocin (30 mg/kg I.P.). Plasma glucose, insulin, and HOMR-IR levels, as well as cytokines, lipid peroxidation, GSH/GSSG, and glucose transporter 1, were determined along with the tight junction proteins occludin (OCLN) and zona occludens 1 (ZO-1). Moreover, the expressions of brain CCAAT/enhancer-binding protein (C/EBPA mRNA), miR-124, glial fibrillary acidic protein (GFAP), and NF-kBp65 were measured alongside the histological investigation. RESULTS: The results revealed that L/ZnO NPs were able to diminish lipid peroxidation, increase the activity of antioxidant enzymes, and reduce inflammation under oxidative stress. Consequently, it was able to reduce hyperglycemia, elevate insulin levels, and improve insulin resistance. Besides, L/ZnO NPs upregulate miR-124, reduce C/EBPA mRNA, increase BCl-2, and inhibit apoptosis. The results indicate that diabetes raises BBB permeability via tight junction protein decline, which is restored following L/ZnO NPs treatment. Luteolin/ZnO NPs regulate miR-124 and microglia polarization by targeting C/EBPA and are expected to alleviate inflammatory injury via modulation of the redox-sensitive signal transduction pathways. Luteolin/ZnO NPs have a novel target for the protection of the BBB and the prevention of neurological complications in diabetes.

Hydrogen sulfide attenuates lung injury instigated by Bisphenol-A via suppressing inflammation and oxidative stress.

The xenoestrogen bisphenol A (BPA), a commonly used industrial chemical, has been linked to endocrine disruption. The point of the study was to consider the effects of chronic BPA exposure on the respiratory system of adult female rats, and the potential mitigating benefits of Sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H2S) administration. Detect biomarkers in Bronchoalveolar lavage fluid (BALF), including total protein content, Total cell counts, Neutrophils %, ICAM (intercellular adhesion molecule)-1 and TGF-ß (Transforming growth factor beta). NaHS significantly reduced pro-inflammatory cytokines (IFN-ß and MCAF,) also reduce (i.e. VCAM-1, VEGF, VIM, MMP-2, MMP-9), and reduced malondialdehyde and augmented activities of SOD and GSH-PX. Notably, H2S induced a marked decrease in the expression levels of p-extracellular signal-regulated protein kinase (p-ERK), p-c-Jun N-terminal kinase (p-JNK), and p-p38, H2S inhibits BPA-induced inflammation and injury in alveolar epithelial cells. These results suggest NaHS may prevent inflammation via the suppression of the ERK/JNK/ p-p38MAPK signaling pathway, Subsequent inhibition of inflammation, epithelial cell injury, and apoptosis may be providing insight into potential avenues for the treatment of lung injury.

Attenuation of N-Nitrosodiethylamine -Induced Hepatocellular Carcinoma by Piceatannol and/or Cisplatin: The Interplay between Nuclear Factor (Erythroid Derived 2)-like 2 and Redox Status.

BACKGROUND: The natural compound's alternative and complementary uses have increased hopes for hepatocellular cancer treatment (HCC). OBJECTS: The goal of this study was to see if Piceatannol (PIC) in combination with cisplatin has a synergistic effect on N, N-nitrosodiethylamine (DEN)-induced HCC in rats. METHODS: Tissue antioxidant enzymes, malondialdehyde (MDA), and nuclear factor erythroid 2 related factors 2 (Nrf2) and tumor necrosis factor α (TNF-α) gene expression were all measured. Nuclear Factor Kabba B (NF-κB) was also tested, as well as hepatic caspase 3 and NAD (P) H quinone oxidoreductase 1 (NQO1). Liver specimens were subjected to histopathological analysis. RESULTS: When compared to the HCC group, piceatannol and/or cisplatin caused a significant improvement in liver function tests, as well as a significant modulation in Nrf2 gene expression and antioxidant enzyme activities, as well as a significant decrease in tissue MDA, TNF-α, NF-κB levels, NQO1 activity, and prompt and caspase-3 activities. When the PIC and/or cisplatin combination was compared to each of these compounds alone, the results were substantial. CONCLUSION: PIC in combination with cisplatin has been shown to have a synergistic anticancer impact through modulating Nrf2 and redox state. In addition, adding PIC to an HCC therapy plan that includes chemotherapeutic medicines may boost the efficacy of cisplatin while reducing its negative effects.

Blastocystis hominis undergoing programmed cell death via cytotoxic gamma irradiation.

Blastocystis hominis is a worldwide common enteric parasite. Its pathogenic potential has not yet been established, although many reports suggest that it may cause the development of various gastrointestinal symptoms. The aim of the present study is to evaluate the destructive effect of different doses of cytotoxic gamma (γ) irradiation combined with and compared to metronidazole (MTZ) on Blastocystis spp. in vitro. The detection of the parasite in the stool specimen was conventionally done by light microscopic examination of direct smears, cultivation, followed by PCR-sequencing. Evaluation of γ-irradiation and MTZ effects on B. hominis was carried out by trypan blue exclusion assay, caspase activity detection, acridine orange staining, DNA fragmentation assay and transmission electron microscopic (TEM) examination. The current study demonstrated that exposure to γ-irradiation in a dose of 0.5 kGray (kGy) significantly (P < 0.05) reduced the viability of B. hominis subtype 2 by 95.2% compared to the untreated and MTZ-treated parasites (87.1%) after 48 h incubation. Combining the same dose of irradiation (0.5 kGy) with MTZ yielded a viability reduction of 94.2% and 94% after 24 and 48 h respectively, which were statistically significant (P < 0.05) compared to MTZ alone. Moreover, our results showed features of programmed cell death in the form of morphological, biochemical, and molecular changes (TEM abnormalities, caspase-like activity, and DNA fragmentation, respectively) with the high doses of γ-irradiation (0.3 and 0.5 kGy) either singly or combined with MTZ. In conclusion, cytotoxic γ-irradiation plays an important role in the inactivation of Blastocystis spp., so, it can be a promising prophylactic water-sterilizing tool against blastocystosis.

Modulation of endoplasmic reticulum stress via sulforaphane-mediated AMPK upregulation against nonalcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is a major health concern. Endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may be targeted to prevent the progress of nonalcoholic fatty liver disease. Sulforaphane (SFN), a sulfur-containing compound that is abundant in broccoli florets, seeds, and sprouts, has been reported to have beneficial effects on attenuating metabolic diseases. In light of this, the present study was designed to elucidate the mechanisms by which SFN ameliorated ER stress, inflammation, lipid metabolism, and insulin resistance - induced by a high-fat diet and ionizing radiation (IR) in rats. In our study, the rats were randomly divided into five groups: control, HFD, HFD + SFN, HFD + IR, and HFD + IR + SFN groups. After the last administration of SFN, liver and blood samples were taken. As a result, the lipid profile, liver enzymes, glucose, insulin, IL-1ß, adipokines (leptin and resistin), and PI3K/AKT protein levels, as well as the mRNA gene expression of ER stress markers (IRE-1, sXBP-1, PERK, ATF4, and CHOP), fatty acid synthase (FAS), peroxisome proliferator-activated receptor-α (PPAR-α). Interestingly, SFN treatment modulated the levels of proinflammatory cytokine including IL-1ß, metabolic indices (lipid profile, glucose, insulin, and adipokines), and ER stress markers in HFD and HFD + IR groups. SFN also increases the expression of PPAR-α and AMPK genes in the livers of HFD and HFD + IR groups. Meanwhile, the gene expression of FAS and CHOP was significantly attenuated in the SFN-treated groups. Our results clearly show that SFN inhibits liver toxicity induced by HFD and IR by ameliorating the ER stress events in the liver tissue through the upregulation of AMPK and PPAR-α accompanied by downregulation of FAS and CHOP gene expression.

Bisphenol-A/Radiation mediated inflammatory response activates EGFR/KRAS/ERK1/2 signaling pathway leads to lung carcinogenesis incidence.

BACKGROUND: Bisphenol (BPA) and ionizing radiation exposure (IR) are potent oxidants that cause free radical induction, leading to signaling pathway activation that alters cell growth. Due to the insufficient knowledge of the impact of BPA and IR on the lungs, the current study determined the impact of BPA and IR on the lung tissue of adult female Wistar rats. METHODS: Forty Wister female rats were used in this study and were randomly divided into four groups. The rats received BPA (150 mg/kg body weight/day for 6 weeks) and were exposed to IR at 2 Gy/week up to 12 Gy for 6 weeks. RESULTS: It was found that BPA and IR possess a harmful effect on the lungs via induction of oxidative stress, confirmed by increasing levels of malondialdehyde (MDA), nitric oxide, myeloperoxidase (MPO), and lactate dehydrogenase (LDH). Exposure to BPA and IR activates inflammatory cytokines TNF-α, IL-6, IL-1ß, growth factors such as TGF-ß, and gastrin-releasing peptides. BPA/IR exposures induced phosphorylated expression p-ERK1/2 and p-MEK1/2 associated with triggering of the GPER/EGFR/KRAS signaling factors, resulting in matrix metalloproteinase-2 and 9 overexpression and the development of lung tumors. Our findings support the causal role of two deleterious environmental pollutants BPA and IR, via the cytotoxicity in the respiratory system in the form of severe lung damage resulting in cancerous cells.

Boswellic acid protects against Bisphenol-A and gamma radiation induced hepatic steatosis and cardiac remodelling in rats: role of hepatic PPAR-α/P38 and cardiac Calcineurin-A/NFATc1/P38 pathways.

Bisphenol-A (BPA) and gamma-radiation are two risky environmental pollutants that human beings are exposed to in everyday life and consequently they threaten human health via inducing oxidative stress, inflammation, and eventually tissue damage. This study aims at appraising the protective effect of Boswellic Acid (BA) (250 mg/kg/day, orally) administration on BPA (150 mg/kg/day, i.p) and γ-irradiation (IR) (3 Gy/week for 4 weeks up to cumulative dose of 12 Gy/experimental course) for 4 weeks-induced damage to liver and heart tissues of rats. The present results indicated a significant improvement against damage induced by BPA and IR revealed in biochemical investigations (hepatic PPAR-α/P38 and cardiac ET-1/Calcineurin-A/NFATc1/P38) and histopathological examination of liver and heart. It could be concluded that BA possesses a protective effect against these two deleterious environmental pollutants which attracted major global concerns due to their serious toxicological impact on human health.

Curative role of mesenchymal stromal cells in chronic pancreatitis: Modulation of MAPK and TGF-ß1/SMAD factors.

BACKGROUND AND OBJECTIVE: Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern. METHODS: This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks. RESULTS: Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination. CONCLUSION: our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.

Mangosteen Hinders Gamma Radiation-Mediated Oxidative Stress and Liver Injury by Down-Regulating TNF-α/NF-κB and Pro-Fibrotic Factor TGF-ß1 Inducing Inflammatory Signaling.

BACKGROUND: Liver injury due to ionizing radiation exposure either accidental or after radiotherapy treatment, may lead to many alterations in proteins expression related to inflammation or apoptosis. Our study investigated the curative effect of Mangosteen (MGS) extract (fruit rind) against ionizing radiation (IR) induced liver damage. METHODS: Hepatotoxicity was induced in Wister rats by exposure to an acute single dose (6 Gy) of IR while MGS was given orally to rats (500 mg/kg bwt) and administered daily for 30 days after irradiation. RESULTS: MGS treatment has significantly attenuated redox imbalance state and toxicity induced by protracted exposure to gamma-rays in liver tissues, which was substantiated by the significant amelioration of liver function tests, MDA contents, antioxidant enzymes (SOD and CAT) activities and NO level. MGS inhibited also the inflammatory markers (TNF-alpha, IL-6 and CRP) and downregulated transcriptional factor NF-Kappa-B/TGF-ß1. These alterations were concomitant with an improvement of the Proliferating cell nuclear antigen (PCNA) which is a protein expressed in the nuclei of cells during cell cycle and is important for both DNA synthesis and DNA repair. These results were confirmed by amelioration in histological and ultrastructural examinations. CONCLUSION: We concluded that MGS could ameliorate via minimizing significantly the amount of oxidative damage, inflammations disturbances and pro-apoptotic alternations induced by IR. MGS may be a promising supplement with protective effects from irradiation-induced injury such as TNF-α/NF-κB/TGF-ß1 management.

The impact of citicoline on brain injury in rats subjected to head irradiation.

Hazard and risk associated with the use of radiotherapy play a crucial role in brain injury with interference via the neuroendocrine activity of the cancer survivors, and there is no effective preventive strategy. We conducted this study to assess the effect of citicoline in biosynthesis variants occurring in the cerebral cortex of rats in response to head γ-irradiation. Bio-analysis includes MDA, 8-OHdG, and NO as oxidation indicators; total antioxidant activity; the inflammatory factors TNF-α, IL-1ß, and amyloid-ß 42 levels; the caspase-3 cell death marker; IGF-I; serum hormones including GH, ACTH, FSH, and LH; and the neurotransmitters acetylcholine, dopamine, and serotonin. We exposed animals to 10 Gy head gamma irradiation followed by citicoline treatment and sustained for 30 days. The animals were sacrificed at the 3rd and 30th day post-irradiation. Citicoline mechanism has been linked to potent radical reduced ability counteracting the oxidative stress-mediated inflammation and apoptosis. Citicoline treatment has normalized the altering recorded in serum hormones associated with a significant modulation in the levels of IGF-1/PI3K/AKT factors. Such improvements have been concomitant with regulated neurotransmitter levels. We could conclude that citicoline may safely be supplemented to avoid both short- and long-term damages to the neuroendocrine disturbances, oxidative stress, inflammation, and apoptosis induced by head irradiation.

Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats.

OBJECTIVE: Chronic Pancreatitis (CP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluating the ability of bone marrow-based mesenchymal stem cell (MSCs) combined with Icariin to restore and regenerate acinar cells in the pancreas of rats suffering chronic pancreatitis. METHODS: Chronic pancreatitis was induced in rats via both L-arginine plus radiation, repeated L-arginine injection (2.5g/Kg body-weight, 1, 4,7,10,13,16,19 days), then, on day 21, rats were exposed to a single dose of gamma-radiation (6 Gy), which exacerbate injury of pancreatic acinar cells. One day after irradiation, rats were treated with either MSCs (1 × 107 /rat, once, tail vein injection) labeled PKH26 fluorescent linker dye and/or Icariin (100 mg/Kg, daily, orally) for 8 weeks. RESULTS: Icariin promotes MSCs proliferation boosting its productivity in vitro. MSCs, and/or icariin treatments has regulated molecular factors TGF-ß/PDGF and promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cell in the tissue, and confirmed by histopathological examination. Moreover, a significant decrease in IL-8 and TNF-α cytokines with significant amelioration of myeloperoxidase activity were noted. As well as, reduction in MCP-1 and collagen type-1 levels along with Hedgehog signaling down-regulating expression in such cells, Patched-1, Smoothened, and GLi-1. CONCLUSION: The potent bioactive therapeutic Icariin combined with MSCs induces a significantly greater improvement, compared to each therapy alone.

Suppression of inflammatory cascades via novel cinnamic acid nanoparticles in acute hepatitis rat model.

Hepatitis was characterized by extreme inflammation and hepatocellular damage. Therefore, the current study aimed to gain insights into the modulation role of Cinnamic acid nanoparticles (CANPs) against acute hepatitis induced by d-Galactosamine and gamma radiation exposure (D-Gal/radiation) in the rat model and to suggest the implied molecular mechanism of CANPs. Acute hepatitis seriousness and the serum enzyme activities of ALT, AST, and ALP have been diminished upon oral administration of CANPs. Besides, the hepatic tissue levels of malondialdehyde (MDA) and nitric oxide (NO) have been significantly decreased, and the total antioxidant activity (TAO) depletion was extremely restored. Furthermore, the reduction of hepatic damage caused by pretreatment with CANPs was accompanied by significant suppression in the levels of hepatic proinflammatory cytokines (TNF-α, IL-1ß, and IL-18), NF-κB, NLRP3, caspase-1 and proapoptotic protein BAX whereas anti-apoptotic protein Bcl-2 level significantly elevated as compared with D-Gal/radiation-induced acute hepatitis (AH) group. Also, CANPs suppress the D-Gal/radiation-induced IL-1ß, IL-18, and ASK1 mRNA gene expression and the protein expression of TLR4 and MyD88 in the hepatic tissue. These biochemical parameters are confirmed by histological examination of the liver tissues. The present results indicated that CANPs can protect the hepatic cells from damage by both its anti-inflammatory and antioxidant influence as well as by modulating oxidation cellular pathways that have contributed to the acute severity of hepatitis. Also, CANPs is capable of suppressing apoptosis. Consequently, Nanoparticles of Cinnamic acid have the medicinal ability to protect the liver from acute hepatitis.

Protective effect of rutin against brain injury induced by acrylamide or gamma radiation: role of PI3K/AKT/GSK-3ß/NRF-2 signalling pathway.

This study was designed to evaluate the effect of rutin on PI3K/AKT-signalling in case of acrylamide or γ-radiation-induced neurotoxicity. To induce brain damage, animals were received acrylamide (25 mg/kg b.wt./orally/day) or 5 Gy of γ-radiation exposure accompanied with an administration of rutin (200 mg/kg b.wt./orally/day). Our data revealed that, compared to acrylamide or γ-radiation, rutin activated PI3K/AKT/GSK-3ß/NRF-2-pathway through increased protein levels of p-PI3K, p-AKT and p-GSK-3ß and up-regulated the expression of NRF-2. This was achieved by modulating MDA, GST, IL-1ß, IL-6 and reduced the interference of ROS with IGF-1 and NGF stimulating the PI3K/AKT-signaling. Furthermore, histopathological examinations of brain tissues showed that rutin has modulated tissue architecture after acrylamide or γ-radiation induced tissue damage. It could be concluded that rutin provides protection effect against acrylamide or γ-radiation-induced neurotoxicity via activation of the PI3K/AKT/GSK-3ß/NRF-2-pathway by altering the phosphorylation state through its ability to scavenge free radicals generation, modulating gene expression and its anti-inflammatory effects.

Synergistic effect of Ebselen and gamma radiation on breast cancer cells.

PURPOSE: To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro. MATERIALS AND METHODS: Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 µg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6 Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-ß), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated. RESULTS: The results showed that the effective dosage of this combination was observed at 25 µg/ml of Ebs with γ-radiation at 6 Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-ß with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed. CONCLUSIONS: We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines.

Gallium Nanoparticle-Mediated Reduction of Brain Specific Serine Protease-4 in an Experimental Metastatic Cancer Model

Purpose: Tumor growth and metastasis depend on angiogenesis; therefore, efforts are being made to develop specific angiogenic inhibitors. Gallium (Ga) is the second most common metal ion, after platinum, used in cancer treatment. Its activities are numerous and various. In the present study, we aimed to investigate the effect of Ga on brain metastasis arising from hepatocellular carcinoma (HCC). Materials and methods: Forty experimental rats (divided into 4 groups) received diethylnitrosamine (DEN) at a dose (20 mg/kg.b.wt.; for 6 weeks) to induce HCC and were treated with Ga nanoparticles (GaNPs) with the bacterium Bacillus licheniformis (1mg/kg.b.wt.). Liver functions (alanine aminotransferase; (ALT), aspartate aminotransferase; (AST) and gamma glutamyl transferase; (GGT) and alpha-fetoprotein (AFP)) were assessed with histopathological examination of liver sections to confirm the induction of HCC. In addtion, brain-specific serine protease 4 (BSSP4), extracellular signal-regulated kinase (ERK), a microtubule-associated protein (Tau), vascular endothelial growth factor (VEGF), vascular cells adhesion molecule-1 (VCAM-1), cytochrome P450 (CYP450), lipid peroxidation (MDA) and glutathione-S-transferase (GST) were measured in brain tissue. Results: GaNPs ranged from 5 to 7 nm. HCC was confirmed by elevation in liver enzymes and AFP. Additionally, histopathological examination of liver showed focal area of anaplastic hepatocytes with other cells forming acini associated with fibroblastic cell proliferation. In brain, compared to the DEN alone group, we found that GaNPs modulated brain metastasis by reducing CYP450 and BSSP4 mRNA, and protein expression of p-ERK and p-Tau, and angiogenesis mediators (VEGF and VCAM-1). Also, GaNPs elevated lipid peroxidation and GST activity. Conclusion: It is concluded that GaNPs may prevent metastasis via inhibition of BSSP4 mRNA expression leading to suppression of a variety of growth factors and cell adhesion molecules involved in tumor growth and angiogenesis.