Effects of Monensin and Rapamycin Combination Therapy on Tumor Growth and Apoptosis in a Xenograft Mouse Model of Neuroblastoma.

Neuroblastoma is the most common pediatric solid tumor originating from the neural crest. New treatment options are needed to improve treatment outcomes and the survival of patients with neuroblastoma. Monensin is an ionophore antibiotic with antiparasitic, antibacterial, and anticancer properties isolated from Streptomyces cinnamonensis. The aim of this study was to investigate the therapeutic effects of single and combined monensin and rapamycin treatments on mTOR (mammalian target of rapamycin) signaling pathway-mediated apoptosis and tumor growth in an SH-SY5Y neuroblastoma cell xenograft model. Control, monensin, rapamycin, and monensin + rapamycin groups were formed in the xenograft neuroblastoma model obtained from CD1 nude mice, and tumor volumes and animal weights were recorded throughout the treatment. In xenograft neuroblastoma tumor tissues, apoptosis was determined by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) and cleaved-caspase 3 immunohistochemistry, and PI3K (phosphoinositide-3-kinase)/AKT/mTOR expression was determined by the immunohistochemistry and immunofluorescence methods. The combination of monensin and rapamycin was to reduce the growth of xenograft neuroblastoma tumor tissues, trigger apoptosis, and suppress the expression of PI3K/AKT/mTOR. A significant increase in apoptotic cell rate was demonstrated in the combination group, supported by cleaved-caspase 3 immunohistochemistry results. In addition, it was reported that the combination treatment regime triggered apoptosis by reducing the expression of phosphorylated PI3K/AKT/mTOR. Our preclinical results may be a precursor to develop new therapeutic approaches to treat neuroblastoma.

Erianin as a Promising Novel Agent in the Treatment of Neuroblastoma: The Anticancer Effects and Underlying Molecular Mechanisms.

BACKGROUND: Erianin is an active dibenzyl compound isolated from Dendrobium officinale and Dendrobium chrysotoxum and there are very few studies on molecular mechanisms and drug targets of erianin. In addition, there is no study investigating the anti-cancer effect of erianin on neuroblastoma cells. OBJECTIVE: The aim of the study is to investigate the anticancer effect of erianin and the underlying mechanism of this effect on SH-SY5Y cells. METHODS: The effects of erianin on cell viability, invasion and migration were determined by XTT, matrigel chamber and wound healing evaluation, respectively. Expression changes of miRNAs (microRNA) and apoptosis-related genes were evaluated by RT-PCR, and the apoptosis rate was supported by Annexin V evaluation. RESULTS: Erianin significantly decreased cell proliferation, invasion and migration. Erianin administration caused apoptosis by significantly increasing caspase-7, FADD (Fas-associated protein with death domain), BID (BH3 Interacting Domain Death Agonist) and DR5 (Death receptor 5) gene expressions. While the rate of total apoptotic cells was 45.35 ± 6.80% in SH-SY5Y cells treated with erianin, it was 0.133 ± 0.05% in the control group (p = 0.000). In addition, erianin administration significantly decreased the expressions of hsa-miR-155-5p (p = 0.014) and hsa-miR-223-3p (p = 0.004). Also, our study demonstrated for the first time the relationship between erianin and mi-RNAs in a cancer cell. CONCLUSION: Our study suggests that erianin may be a natural, safe and easily accessible drug candidate that can be used in the treatment of neuroblastoma.

Low-intensity low-frequency pulsed ultrasound ameliorates sciatic nerve dysfunction in a rat model of cisplatin-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy is a neurological complication that frequently occurs during chemotherapeutic intervention, resulting in damaged myelin sheath, motor weakness and/or sensory impairment. This study aims to investigate the therapeutic efficiency of low-intensity pulsed low-frequency ultrasound on cisplatin-induced peripheral neuropathy. Rats were randomly divided into five experimental groups as control, cisplatin administration, 10 mg/kg melatonin treatment after cisplatin administration, 1 MHz frequency 0.5 W/cm2 pulsed ultrasound treatment after cisplatin administration and 1 MHz frequency 1.5 W/cm2 pulsed ultrasound treatment after cisplatin administration. Chemical neuropathy was induced by the injection of 3 mg/kg/week of cisplatin (i.p.) for 5 weeks. Afterwards, melatonin and pulsed ultrasound treatments were applied for 15 consecutive days. Cisplatin administration resulted in a decrease in nociceptive pain perception and nerve conduction velocities together with a decrease in myelin thickness and diameters of axons and myelinated fibers, indicating a dysfunction and degeneration in sciatic nerves. In addition, cisplatin administration led to a decrease, in superoxide dismutase activity, and an increase in malondialdehyde and IL-1ß levels together with an increase in caspase-3 protein expression levels and a decrease in Bcl-2 and Parkin levels. The ultrasound treatments resulted in an increase in nociceptive pain perception and sciatic nerve conduction; led to a decrease in oxidative stress and inflammation, restored nerve degeneration and regulated apoptosis and mitophagy. Taken together, low-intensity pulsed low-frequency ultrasound was efficient in restoring the alterations attributable to cisplatin-induced peripheral neuropathy, and warrants further investigations.

Antiinflammatory effects of adalimumab, tocilizumab, and steroid on lipopolysaccharide-induced lung injury.

BACKGROUND: Acute lung injury (ALI) is a major cause of death in the intensive care unit. Lipopolysaccharide (LPS) induced lung injury is the most widely used experimental ALI model and provides opportunities for new targeting therapy. In this study, we investigated the effects of tocilizumab, adalimumab, and methylprednisolone in LPS-induced acute lung injury. METHODS: Lung injury was established by intratracheal instillation of LPS. The rats were randomly divided into six groups: LPS, control, and treatment groups (adalimumab, tocilizumab, methylprednisolone, adalimumab + tocilizumab). Bronchoalveolar lavage (BAL) and lung tissues were collected at 48 h and 96 h following LPS administration from each group. For histological analysis, hematoxylin-eosin (H&E) staining was performed. The sections were obtained for immunohistochemical analysis. IL-6 and TNF-alpha immunoreactivity were measured. RESULTS: Intratracheal LPS application resulted in inflammatory cell infiltration of interstitial and alveolar spaces and thickening of the alveolar wall. All treatment groups showed significantly amelioration compared to LPS at 48 h. Interestingly, adalimumab and adalimumab + tocilizumab groups showed a significant amelioration of the lung histoarchitecture, compared to the prednisolone group at 96 h (p = 0.028, p = 0.025, respectively). Compared to the control group, LPS stimulation resulted in a significant increase in IL-6 and TNF-alpha immunoreactivity (p < 0.001). IL-6 and TNF-alpha expression were markedly reduced in all treatment groups at 48 h but the reduction was greater in the adalimumab and tocilizumab group than in the steroid. Administration with adalimumab and/or tocilizumab effectively decreased expression of TNF-alpha (p = 0.001) and IL-6 (p < 0.001) at 96 h, but prednisolone did not exert an effective decrease (p > 0.05). DISCUSSION: Adalimumab and/or tocilizumab significantly reduce the release of proinflammatory cytokines and improve the tissue inflammation in the experimental model of ALI. Our results suggest that adalimumab and/or tocilizumab have a more potent antiinflammatory effect on lung injury than the steroid.

Protective Effects of Quercetin on Necrotizing Enterocolitis in a Neonatal Rat Model.

INTRODUCTION: Necrotizing enterocolitis (NEC) is one of the major health problems of newborn period. To date, a large amount of chemicals have been tested for NEC and some showed limited beneficial effects. The research for better results still continues. This study aims to investigate the effects of quercetin (QE) on NEC treatment in rats. METHODS: Newborn rats were divided into control, NEC, and NEC + QE groups. In NEC and NEC + QE groups, experimental NEC was induced. NEC + QE group animals were also given QE. Weight changes of the animals were recorded, and serum total antioxidant status (TAS), total oxidant status (TOS), malondialdehyde (MDA), and glutathione (GSH) levels were measured. Histologic evaluation of the distal ileum and the terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. RESULTS: A significant increase in the TAS levels was observed in NEC + QE group. Only NEC group exhibited significantly higher TOS and MDA levels and lower GSH levels. Rats in the NEC + QE group had better histopathology and less apoptosis than NEC group. CONCLUSION: QE is effective in enhancing antioxidant defense mechanism, limiting oxidative stress, reducing intestinal damage, and preventing NEC development.

In vivo effects of curcumin on the paraoxonase, carbonic anhydrase, glucose-6-phosphate dehydrogenase and ß-glucosidase enzyme activities in dextran sulphate sodium-induced ulcerative colitis mice.

Increases in the risk of infections and malignancy due to immune suppressive therapies of inflammatory bowel diseases (IBDs) have led the researchers to focus on more nontoxic and acceptable natural products like curcumin. Here we investigate whether prophylactic and therapeutic application of the curcumin alters the enzyme activities of paraoxonase (PON), carbonic anhydrase (CA), glucose-6-phosphate dehydrogenase (G6PD) and cytosolic ß-glucosidase in dextran sulphate sodium (DSS)-induced ulcerative colitis mice. Prophylactic application of curcumin resulted in higher MPO activity, less body weight loss and longer colon lengths compared to therapeutic group indicating preventive role of curcumin in IBDs. DSS-induced decrease in liver and serum PON activities were completely recovered by prophylactic administration of curcumin. DSS-induced reduction in liver cytosolic ß-glucosidase activity was not affected by curcumin neither in the prophylactic group nor in the therapeutic group. Erythrocyte CA activity was significantly increased in curcumin groups, however no remarkable change in G6PD activity was observed.