Ondansetron or beta-sitosterol antagonizes inflammatory responses in liver, kidney, lung and heart tissues of irradiated arthritic rats model.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder mainly affecting joints, yet the systemic inflammation can influence other organs and tissues. The objective of this study was to unravel the ameliorative capability of Ondansetron (O) or ß-sitosterol (BS) against inflammatory reactions and oxidative stress that complicates Extra-articular manifestations (EAM) in liver, kidney, lung, and heart of arthritic and arthritic irradiated rats. METHODS: This was accomplished by exposing adjuvant-induced arthritis (AIA) rats to successive weekly fractions of total body γ-irradiation (2 Gray (Gy)/fraction once per week for four weeks, up to a total dose of 8 Gy). Arthritic and/or arthritic irradiated rats were either treated with BS (40 mg/kg b.wt. /day, orally) or O (2 mg/kg) was given ip) or were kept untreated as model groups. RESULTS: Body weight changes, paw circumference, oxidative stress indices, inflammatory response biomarkers, expression of Janus kinase-2 (JAK-2), Signal transducer and activator of transcription 3 (STAT3), high mobility group box1 (HMGB1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), as well as pro- and anti-inflammatory mediators in the target organs, besides histopathological examination of ankle joints and extra-articular tissues. Treatment of arthritic and/or arthritic irradiated rats with BS or O powerfully alleviated changes in body weight gain, paw swelling, oxidative stress, inflammatory reactions, and histopathological degenerative alterations in articular and non-articular tissues. CONCLUSION: The obtained data imply that BS or O improved the articular and EAM by regulating oxidative and inflammatory indices in arthritic and arthritic irradiated rats.

Fractionated whole body γ-irradiation aggravates arthritic severity via boosting NLRP3 and RANKL expression in adjuvant-induced arthritis model: the mitigative potential of ebselen.

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease associated with oxidative stress that causes excruciating pain, discomfort, and joint destruction. Ebselen (EB), a synthesized versatile organo-selenium compound, protects cells from reactive oxygen species (ROS)-induced injury by mimicking glutathione peroxidase (GPx) action. This study aimed to investigate the antioxidant and anti-inflammatory effects of EB in an arthritic irradiated model. This goal was achieved by subjecting adjuvant-induced arthritis (AIA) rats to fractionated whole body γ-irradiation (2 Gy/fraction once per week for 3 consecutive weeks, for a total dose of 6 Gy) and treating them with EB (20 mg/kg/day, p.o) or methotrexate (MTX; 0.05 mg/kg; twice/week, i.p) as a reference anti-RA drug. The arthritic clinical signs, oxidative stress and antioxidant biomarkers, inflammatory response, expression of NOD-like receptor protein-3 (NLRP-3) inflammasome, receptor activator of nuclear factor κB ligand (RANKL), nuclear factor-κB (NF-κB), apoptotic indicators (caspase 1 and caspase 3), cartilage integrity marker (collagen-II), and histopathological examination of ankle joints were assessed. EB notably improved the severity of arthritic clinical signs, alleviated joint histopathological lesions, modulated oxidative stress and inflammation in serum and synovium, as well as reduced NLRP-3, RANKL, and caspase3 expression while boosting collagen-II expression in the ankle joints of arthritic and arthritic irradiated rats with comparable potency to MTX. Our findings suggest that EB, through its antioxidant and anti-inflammatory properties, has anti-arthritic and radioprotective properties in an arthritic irradiated model.

FA-HA-Amygdalin@Fe2O3 and/or γ-Rays Affecting SIRT1 Regulation of YAP/TAZ-p53 Signaling and Modulates Tumorigenicity of MDA-MB231 or MCF-7 Cancer Cells.

BACKGROUND: Breast cancer (BC) has a complex and heterogeneous etiology, and the emergence of resistance to conventional chemo-and radiotherapy results in unsatisfactory outcomes during BC treatment. Targeted nanomedicines have tremendous therapeutic potential in BC treatment over their free drug counterparts. OBJECTIVE: Hence, this study aimed to evaluate the newly fabricated pH-sensitive multifunctional FAHA- Amygdalin@Fe2O3 nano-core-shell composite (AF nanocomposite) and/or γ-radiation for effective localized BC therapy. METHODS: The physicochemical properties of nanoparticles were examined, including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy. MCF-7 and MDA-MB-231 cells were treated with AF at the determined IC50 doses and/or exposed to γ-irradiation (RT) or were kept untreated as controls. The antitumor efficacy of AF was proposed via assessing anti-proliferative effects, cell cycle distribution, apoptosis, and determination of the oncogenic effectors. RESULTS: In a bio-relevant medium, AF nanoparticles demonstrated extended-release characteristics that were amenable to acidic pH and showed apparent selectivity towards BC cells. The bioassays revealed that the HA and FA-functionalized AF markedly hindered cancer cell growth and enhanced radiotherapy (RT) through inducing cell cycle arrest (pre-G1 and G2/M) and increasing apoptosis, as well as reducing the tumorigenicity of BCs by inhibiting Silent information regulation factor 1 (SIRT1) and restoring p53 expression, deactivating the Yes-associated protein (YAP)/ Transcriptional coactivator with PDZ-binding motif (TAZ) signaling axis, and interfering with the tumor growth factor- ß(TGF- ß)/SMAD3 and HIF-1α/VEGF signaling hub while up-regulating SMAD7 protein expression. CONCLUSION: Collectively, the novel AF alone or prior RT abrogated BC tumorigenicity.

Trans-resveratrol alleviates hepatic and renal injury in γ-irradiated rats.

BACKGROUND: Although ionizing radiation (IR) has been of immense value to human life due to its involvement in several fields, it doesn't eliminate that exposure to IR results in an array of biological consequences, including oxidative stress, inflammation, and death. Thus, this study aimed to explore the curative effect of trans-Resveratrol (t-Res) on hepatic and renal injury in a rat model exposed to single and fractionated doses of γ-rays. METHODS: Rats exposed to a single dose of IR (6 Gy, as an acute effect) or a fractionated dose of IR (2 Gy/time/3 days, day after day; to imitate a chronic impact) were treated with t-Res. Then, the radio-protective effect of t-Res was investigated via biochemical and histological estimations in the liver and kidney of rats in the different groups. RESULTS: The data displayed a significant amelioration in biochemical and histological indices in the liver and kidney of rats exposed to IR doses and treated with t-Res. Particularly, t-Res reduced the oxidative stress milieu through decreasing HIF-1α, ROS, and MDA levels associated with increased CAT activity and Nrf-2 gene expression. Also, t-Res improved the inflammatory status via a decrease in TNF-α, NF-κB, SOCS-3, and HSP-70 genes expression linked with elevations in SIRT-1 and P53 genes expression. CONCLUSION: It could be concluded that t-Res had hepatoprotective and renoprotective effects against the deleterious consequences of γ-rays exposure due to its antioxidant and anti-inflammatory properties.

Concerted regulation of OPG/RANKL/ NF­κB/MMP-13 trajectories contribute to ameliorative capability of prodigiosin and/or low dose γ-radiation against adjuvant- induced arthritis in rats.

BACKGROUND: Prodigiosin (PDG) is a microbial red dye with antioxidant and anti-inflammatory properties, although its effect on rheumatoid arthritis (RA) remains uncertain. Also, multiple doses of low dose γ- radiation (LDR) have been observed to be as a successful intervention for RA. Thus, the purpose of this study was to investigate the ameliorative potential of PDG and/or LDR on adjuvant-induced arthritis (AIA) in rats. METHODS: The anti-inflammatory and anti-arthritic effects of PDG and/or LDR were examined in vitro and in vivo, respectively. In the AIA model, the arthritic indexes, paw swelling degrees, body weight gain, and histopathological assessment in AIA rats were assayed. The impact of PDG (200 µg/kg; p.o) and/or LDR (0.5 Gy) on the levels of pro- and anti-inflammatory cytokines (IL-1ß, TNF-α, IL-6, IL-18, IL-17A, and IL-10) as well as the regulation of osteoprotegrin (OPG)/ receptor activator of nuclear factor κB ligand (RANKL)/ nuclear factor-κB (NF-κB)/MMP-13 pathways was determined. Methotrexate (MTX; 0.05 mg/kg; twice/week, i.p) was administered concurrently as a standard anti-arthritic drug. RESULTS: PDG and/or LDR markedly diminished the arthritic indexes, paw edema, weigh loss in AIA rats, alleviated the pathological alterations in joints, reduced the levels of pro-inflammatory cytokines IL-1ß, TNF-α, IL-6, IL-18, IL-17A, and RANKL in serum and synovial tissues, while increasing anti-inflammatory cytokines IL-10 and OPG levels. Moreover, PDG and/or LDR down-regulated the expression of RANKL, NF-κBp65, MMP13, caspase-3, and decreased the RANKL/OPG ratio, whereas OPG and collagen II were enhanced in synovial tissues. CONCLUSION: PDG and/or LDR exhibited obvious anti-RA activity on AIA.

Withania somnifera (Ashwagandha) root extract counteract acute and chronic impact of γ-radiation on liver and spleen of rats.

The exposure to ionizing radiation has become inescapably because of increased dependence on radiation to execute works in different fields and also its influences on biological systems. Thus, the current study aimed at examination of the radio-protective effect of the natural ashwagandha (Ag) against acute and chronic doses of γ-radiation on liver and spleen of rats. The impact of Ag was inspected in rats exposed to acute exposure of 8 Gy (single dose) or to chronic exposure of 8 Gy (2 Gy every other day for 4 times). The data obtained reveals significant amelioration of the redox status (MDA, GSH and ROS) in spleen and liver tissues of rats treated with Ag and exposed to the 2-different modes of γ-radiation. Besides, the changes in inflammatory responses assessed by measurements of IL-17, IL-10 and α7-nAchR are less pronounced in rats received Ag and γ-radiation compared to irradiated rats. Further, the measurements of tissues structural damage markers (MMP-2, MMP-9 and TIMP-1) pointed to benefit of Ag against γ-radiation. The histopathological investigation of spleen and liver tissues confirmed this ameliorating action of Ag counter to γ-radiation hazards. It could be suggested that Ashwagandha could exerts radio-protective influences because of its antioxidants and anti-inflammatory capabilities.

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.

Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core-Shell-Radiosensitizer for Breast Cancer Therapy.

Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA-FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.

Influence of Ce3+ Substitution on Antimicrobial and Antibiofilm Properties of ZnCexFe2-xO4 Nanoparticles (X = 0.0, 0.02, 0.04, 0.06, and 0.08) Conjugated with Ebselen and Its Role Subsidised with γ-Radiation in Mitigating Human TNBC and Colorectal Adenocarcinoma Proliferation In Vitro.

Cancers are a major challenge to health worldwide. Spinel ferrites have attracted attention due to their broad theranostic applications. This study aimed at investigating the antimicrobial, antibiofilm, and anticancer activities of ebselen (Eb) and cerium-nanoparticles (Ce-NPs) in the form of ZnCexFe2-XO4 on human breast and colon cancer cell lines. Bioassays of the cytotoxic concentrations of Eb and ZnCexFe2-XO4, oxidative stress and inflammatory milieu, autophagy, apoptosis, related signalling effectors, the distribution of cells through the cell-cycle phases, and the percentage of cells with apoptosis were evaluated in cancer cell lines. Additionally, the antimicrobial and antibiofilm potential have been investigated against different pathogenic microbes. The ZOI, and MIC results indicated that ZnCexFe2-XO4; X = 0.06 specimen reduced the activity of a wide range of bacteria and unicellular fungi at low concentration including P. aeruginosa (9.5 mm; 6.250 µg/mL), S. aureus (13.2 mm; 0.390 µg/mL), and Candida albicans (13.5 mm; 0.195 µg/mL). Reaction mechanism determination indicated that after ZnCexFe2-xO4; X = 0.06 treatment, morphological differences in S.aureus were apparent with complete lysis of bacterial cells, a concomitant decrease in the viable number, and the growth of biofilm was inhibited. The combination of Eb with ZFO or ZnCexFe2-XO4 with γ-radiation exposure showed marked anti-proliferative efficacy in both cell lines, through modulating the oxidant/antioxidant machinery imbalance, restoring the fine-tuning of redox status, and promoting an anti-inflammatory milieu to prevent cancer progression, which may be a valuable therapeutic approach to cancer therapy and as a promising antimicrobial agent to reduce the pathogenic potential of the invading microbes.

Modulatory effect of methylsulfonylmethane against BPA/γ-radiation induced neurodegenerative alterations in rats: Influence of TREM-2/DAP-12/Syk pathway.

AIMS: Methylsulfonylmethane (MSM), is an organosulfur compound, has many health benefits. Bisphenol-A (BPA) and γ-radiation (R) are two risky environmental contaminants that human beings are exposed to in everyday life. This work aims at unveiling the modulatory role of MSM in combating BPA and R co-exposure induced neurodegenerative disorder (Alzheimer's (AD)-mimic neurotoxicity). MAIN METHODS: Female rats were randomly divided into five groups. One group was normal control and the other four groups were subjected to subacute BPA intoxication and/or exposed to fractionated weekly doses of R for 4 weeks and either untreated or treated with MSM concomitantly. KEY FINDINGS: BPA and R co-exposure induced typical hallmarks of neurodegenerative disorders as revealed by tremendously elevated oxidative stress, extensive neuroinflammation (tumor necrosis factor -α and interleukin-1ß), elevated AD markers (amyloid-beta (Aß42), acetylcholinesterase (AchE) activity and tau-phosphorylation) in cortex and hippocampus as well as up-regulation of microglial pro-inflammatory triggering receptor expressed on myeloid cell-2(TREM-2)/DNAX-activating protein of 12 kDa (DAP-12)/spleen-tyrosine kinase (Syk) pathway and its downstream targets (PLC-γ/DAG/p38-MAPK) in hippocampus. Also, neurodegenerative lesions were revealed in histopathological examination of cortex and hippocampus coupled with marked Aß deposition in hippocampus. Whereas, MSM treatment improved histopathological insults and ameliorated level of oxidative stress, neuroinflammation and AD markers as well as modulated TREM-2/DAP-12/Syk pathway. SIGNIFICANCE: Our data suggest that MSM afforded neuroprotection against BPA and R; supporting its potential application in the associated neurodegenerative disorders.

Hyaluronan as a mediator for the hepatoprotective effect of Diosmin/Hesperidin complex.

Daflon is a phlebotonic drug widely used in chronic venous or lymphatic insufficiency. This study designed to investigate the relation of daflon with hyaluronan as a mediator for the hepatoprotective effect against Carbon tetrachloride (CCl4) and/or γ-radiation induced liver damage. Animals of this study were administered CCl4 (1 ml/kg b.wt.), exposed to γ-radiation (1Gy) and treated with daflon (100 mg/kg/day). Our results showed the ameliorative effect of daflon on cytochrome P450 (CYT P450), lipid peroxidation (MDA), liver enzymes (aspartate amino transferase; AST, alanine aminotransferase; ALT and gamma glutamyl transferase; γ-GT), antioxidant capacity (reduced glutathione; GSH and glutathione per oxidase; GPx), inflammatory markers (C-reactive protein; CRP and interlukin- 6; IL-6), alpha-fetoprotein (AFP) and extra cellular matrix proteins (hyaluronan; HA and hyaluronidase; HAase) which was supported by histopathological examination of liver sections compared to the damage induced in CCL4 and/or rats exposed to radiation. It could be concluded that the hepatoprotective effect of daflon is mediated via antioxidant and anti-inflammatory activity in addition to preserving native tissue hyaluronan by preventing its degradation.

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.