Cytokine storm modulation using cholecalciferol and low dose gamma radiation in Escherichia coli infected mice.

This work investigates the efficiency of cholecalciferol and low dose gamma radiation in modulating cytokine storm through their impact on inflammatory and anti-inflammatory cytokine and protecting against lung and liver injuries. Male Swiss albino mice were exposed to 0.2 Gy gamma radiation/week for four consecutive weeks then injected intraperitoneally (i.p) with a single dose of 8.3 × 106 CFU Escherichia coli/g b.w. then injected i.p. with 1.0 mg/kg cholecalciferol (Vit D3) for 7 days starting 4 h after E. coli injection. The results revealed that Cholecalciferol and low dose gamma radiation caused significant depletion in the severity of E. coli infection (colony forming unit per milliliter), log10 of E. coli, Tumor necrosis factor alpha, Interleukin 6, VEGF, alanine aminotransferase, and aspartate aminotransferase levels and significant elevation in IL-10, IL-4, and HO-1. Immunohistochemical analysis of caspase-3 expression in lung tissue section showed low caspase-3 expression in cholecalciferol and low dose gamma radiation treated group. Histopathological examinations were performed in both lung and liver tissues which also emphasis the biochemical findings. Our results exhibit the importance of cholecalciferol and low dose gamma radiation in improving liver function and providing anti-inflammatory response in diseases causing cytokine storm.

Antitumor Activity of Chitosan-Coated Iron Oxide Nanocomposite Against Hepatocellular Carcinoma in Animal Models.

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. Chitosan-coated iron oxide nanocomposite (Fe3O4/Cs) is a promising bio-nanomaterial for many biological applications. The objective of this research was to evaluate the anticancer efficacy of Fe3O4/Cs against HCC in animal models. Fe3O4 nanoparticles were prepared and added to chitosan solution; then, the mixture was exposed to gamma radiation at a dose of 20 kGy. Rats have received diethylnitrosamine (DEN) orally at a dose of 20 mg/kg body weight 5 times per week during a period of 10 weeks to induce HCC and then have received Fe3O4/Cs intraperitoneal injection at a dose of 50 mg/kg body weight 3 times per week during a period of 4 weeks. After the last dose of Fe3O4/Cs administration, animals were sacrificed. DEN induced upregulation of PI3K/Akt/mTOR and MAPK (ERK, JNK, P38) signaling pathways and inflammatory markers (TLR4, iNOS, and TNF-α). DEN also decreases cleaved caspase-3 and increases liver enzymes (ALT, AST, and GGT) activities. Administration of Fe3O4/Cs significantly ameliorated the above-mentioned parameters.

A nano based approach to alleviate cisplatin induced nephrotoxicity.

BACKGROUND AND OBJECTIVE: Cisplatin, an effective drug against cancer, commonly induces nephrotoxicity; limiting its therapeutic efficacy and application. In this study, Cisplatin NanoComposite (Cis NC) was formulated successfully from irradiated chitosan coated Cisplatin and MgO nanoparticles (CHIT/Cis/MgO NPs) to promote cisplatin release in a more sustained manner to improve therapeutic efficacy via the reduction of its nephrotoxicity. To compare the relative induced renal toxicity of cisplatin with Cisplatin NanoComposite, histological and biochemical mechanisms underlying nephrotoxicity were investigated. METHODS: Thirty rats were equally separated to three groups, first group received saline injections and adjusted as the control group, the second group was injected intra-peritoneal with cisplatin 0.64 mg/kg b. wt./day for 6 weeks, the third group was injected intra-peritoneal with Cis NC 5.75 mg/kg b. wt. daily for 6 weeks. RESULTS: Cisplatin-induced renal functional impairment and histopathological damages in the kidney; also, cisplatin disrupted the balance of the redox system in renal tissue, stimulated the inflammatory reactions in the kidney via triggering signal transducer and activator of transcription-1 (STAT1) dependent pathways. Moreover, Cisplatin-induced activation of mammalian target of rapamycin mTOR and inactivation of AMPK/PI3K/Akt signal pathway, and was coupled with induction of p53 activity and the executioner caspase3 to induce apoptotic renal cell death. On the other hand, Cis NC exerted a minimal stimulatory effect on apoptotic and inflammatory signal cascade with negligible renal functional and morphological alterations. CONCLUSION: We postulated that Cis NC may be a valued possible drug to decrease the cytotoxicity of cisplatin thus reserves the renal function and structure.

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.

Gamma Radiation-Attenuated Toxoplasma gondii Provokes Apoptosis in Ehrlich Ascites Carcinoma-Bearing Mice Generating Long-Lasting Immunity.

PURPOSE: Pathological angiogenesis and apoptosis evasions are common hallmarks of cancer. A different approach to the antitumor effect of parasitic diseases caused by certain protozoans and helminthes had been adopted in recent years as they can affect many cancer characteristics. The present work is an attempt to assess the effect of gamma radiation-attenuated Toxoplasma gondii ME49 as an antiapoptotic and angiogenic regulator modifier on tumor growth aimed at improving cancer protective protocols. METHODS: Attenuated Toxoplasma gondii ME49 was administered orally to mice 2 weeks before inoculation with Ehrlich ascites carcinoma to allow stimulation of the immune response. Hepatic histopathology and immune responses were determined for each group. RESULTS: Marked suppression of the tumor proliferation with induction of long-lasting immunity by stimulating interferon γ and downregulating transforming growth factor ß. The level of tumor promoting inflammatory markers (STAT-3 and tumor necrosis factor α), the angiogenic factors (vascular endothelial growth factor A, integrin, and matrix metallopeptidase 2 and matrix metallopeptidase 9), as well as nitric oxide concentration were significantly decreased. This was collimated with an improvement in apoptotic regulators (cytochrome-c, Bax, Bak, and caspase 3) in liver tissues of vaccinated mice group compared to Ehrlich ascites carcinoma-bearing one. Moreover, the histopathological investigations confirmed this improvement. CONCLUSION: Hence, there is an evidence of potency of radiation attenuated Toxoplasma vaccine in immune activation and targeting tumor cell that can be used as a prophylactic or an adjuvant in combination with chemotherapeutic drugs.

Immunomodulatory activity of gamma radiation-attenuated Toxoplasma gondii in adjuvant arthritic mice.

There is growing evidence that some parasitic infections can impact a variety of autoimmune diseases by disease-inducing or protecting capacities. Anti-inflammatory molecules secreted by Toxoplasma gondii and other parasites are capable of preventing some autoimmune disease like arthritis, lupus nephritis and systemic lupus erythematosus by acting on the immune system. Here we aimed to evaluate the protective efficacy of vaccination with Toxoplasma gondii (T. gondii), either gamma radiation-attenuated or not, on an adjuvant arthritis mouse model. Forty female Swiss albino mice were conducted in experiment divided into normal control; mice were injected with Complete Freund's adjuvant (CFA) into the right hind paws; mice vaccinated with irradiated T. gondii in the 3rd group and un-irradiated T. gondii in the 4th group then were injected two weeks later with CFA. Histopathological changes and IL-17, STAT6 and ROR-γ levels in the joints, as well as serum survivin and Anti-CCP, were evaluated. Also, the splenic production of TGF-ß1, TGF-ßR, IL-23, IL-1ß, IFN-γ, TFN-∞, NFKß, MMP1 and MMP3 were assessed. Results exhibited an enhancement of the histopathological changes with diminished the rise of IL-17, STAT 6 and ROR- γ within the joints of both vaccinated groups. Also, serum survivin and Anti-CCP, as well as splenic inflammatory cytokines were reduced. It can be concluded that vaccination with un-irradiated or radiation-attenuated T. gondii exerted a protective effect against adjuvant arthritis with better pathological achievement in the radiation-attenuated vaccinated group. Using gamma radiation-attenuated parasite to exclude the delirious effects of imposing infection of live one may pave the way to new preventative modality against rheumatoid arthritis.