Sildenafil improves radiation-induced oral mucositis by attenuating oxidative stress, NF-κB, ERK and JNK signalling pathways.

Radiation-induced oral mucositis is a common and dose-limiting complication of head and neck radiotherapy with no effective treatment. Previous studies revealed that sildenafil, a phosphodiesterase 5 inhibitor, has anti-inflammatory and anti-cancer effects. In this study, we investigated the effect of sildenafil on radiation-induced mucositis in rats. Two doses of radiation (8 and 26 Gy X-ray) were used to induce low-grade and high-grade oral mucositis, separately. A control group and three groups of sildenafil citrate-treated rats (5, 10, and 40 mg/kg/day) were used for each dose of radiation. Radiation increased MDA and activated NF-κB, ERK and JNK signalling pathways. Sildenafil significantly decreased MDA level, nitric oxide (NO) level, IL1ß, IL6 and TNF-α. The most effective dose of sildenafil was 40 mg/kg/day in this study. Sildenafil also significantly inhibited NF-κB, ERK and JNK signalling pathways and increased bcl2/bax ratio. In addition, high-dose radiation severely destructed the mucosal layer in histopathology and led to mucosal cell apoptosis in the TUNEL assay. Sildenafil significantly improved mucosal structure and decreased inflammatory cell infiltration after exposure to high-dose radiation and reduced apoptosis in the TUNEL assay. These findings show that sildenafil can improve radiation-induced oral mucositis and decrease the apoptosis of mucosal cells via attenuation of inflammation and oxidative stress.

Treatment Parameters of Photobiomodulation in the Prevention of Non-surgical Cancer Treatment-Induced Oral Mucositis: A Review of Preclinical Studies.

Introduction: The most important side effect after non-surgery cancer treatment (NSCT) is oral mucositis (OM) which degrades the quality of life. Using photobiomodulation (PBM), formerly known as low-level laser therapy (LLLT), in the prevention of NSCT-induced OM was widely studied. Hence, this review evaluates the efficacy of optical treatment parameters behind the working process of PBM in preventing NSCT-induced OM in preclinical studies. Methods: Using the PubMed, Scopus and Embase databases, the present study systematically reviewed existing preclinical studies for optical treatment parameters of PBM in preventing NSCT-induced OM in experimental models without restriction on the year of publication. Results: In total, 51 articles were recognized during the search of the literature, and only 16 research papers were included in this review, taking into consideration the inclusion as well as exclusion benchmarks. The reviewed studies showed that a consensus has yet to be reached on the optimal PBM treatment parameters in preventing NSCT-induced OM. However, a wavelength of 660 nm, a power density of 40 mW as well as fluence which ranged between 2 and 6 J/cm2 were mostly utilized in the included studies. Furthermore, the severity of NSCT-induced OM was reduced following PBM application with no reported severe side effects. Conclusion: The efficacy of PBM with the associated optical parameters is a promising strategy in preventing NSCT-induced OM. However, the optimal parameters of PBM need to be investigated.

Sumatriptan alleviates radiation-induced oral mucositis in rats by inhibition of NF-kB and ERK activation, prevention of TNF-α and ROS release.

OBJECTIVES: Oral mucositis caused by radiation therapy is a common problem in cancer patients, especially those with head and neck cancer. Numerous experimental and clinical studies have attempted to find a drug to alleviate oral mucositis. Sumatriptan, is conventionally used to treat migraine attack and cluster headache. Recently, low doses have been shown to have anti-inflammatory properties. In this study we aimed to measure the effect of sumatriptan on experimental radiotherapy-induced oral mucositis. MATERIAL AND METHODS: This study evaluates the use of sumatriptan 0.3 and 1 mg/kg in radiation-induced oral mucositis. In order to induce oral mucositis, six rats from each group received 8-Gy of X-ray in a single session. Likewise, three rats from each group received 26-Gy of X-ray. The latter dose of X-ray was used for inducing severe mucositis and apoptosis evaluation by TUNEL assay, while the first dose was used for histopathological and molecular assessments. On 8th day after irradiation, specimens were collected from their tongues for histology, TUNEL and molecular assessments. RESULTS: Radiation caused mucosal atrophy, derangement of the tissue and vasodilation. Sumatriptan significantly decreased histopathological score and alleviated mucosal atrophy. As well, there was no evidence of vasodilation in the sumatriptan group. Likewise, sumatriptan decreased the increased level of NF-kB and prevented its activation as well as ERK phosphorylation. In addition, Sumatriptan-treated rats had lower tissue level of TNF-α, reactive oxygen species and fewer apoptotic cells in TUNEL assay. CONCLUSION: Based on study results, sumatriptan mitigate radiation-induced oral mucositis by inhibiting NF-kB, ERK and limiting the release of TNF-α, oxidative stress factor and apoptosis.

Evaluation of targeted curcumin (CUR) loaded PLGA nanoparticles for in vitro photodynamic therapy on human glioblastoma cell line.

In this study, antibody-conjugated biodegradable polymeric nanoparticles were developed to enhance the photodaynamic efficiency of curcumin (CUR) on glioblastoma tumor cells. Poly (D, l-lactic-co-glycolic acid) nanoparticles (PLGA NPs) were synthesized and stabilized by polyvinyl alcohol (PVA). Poly(ethylene-alt-maleic anhydride) (PEMA) was used to provide carboxyl groups on the surface of NPs. The CUR or FITC (fluorescein isothiocyanate) was encapsulated in PLGA NPs using the nanoprecipitation method. The carboxylic groups on the surface of the PLGA NPs were covalently conjugated to the amino groups of a monoclonal antibody against EGFRvIII (A-EGFRvIII-f). The prepared NPs were fully characterized by Zetasizer, scanning electron microscope (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR), and then entrapment efficiency (EE), drug loading efficiency (DLE), CUR release, cell internalization, intrinsic cytotoxicity, and phototoxicity were evaluated. Furthermore, the effect of monoclonal antibody (MAb) on the tyrosine phosphorylation of EGFRvIII after photodynamic therapy (PDT) was assessed. The immunoreactivity of the antibody in MAb-PLGA NPs was preserved during the process of conjugation. The selective cellular internalization of MAb-PLGA NPs (FITC or CUR loaded) into the DKMG/EGFRvIII cells (EGFRvIII overexpressed human glioblastoma cell line) in comparison with DK-MGlow (human glioblastoma cell line with low level of EGFRvIII) was also confirmed. MAb-CUR-PLGA NPs were able to show more effective photodynamic toxicity (56% vs. 24%) on the DKMG/EGFRvIII cells compared to CUR-PLGA NPs. These results suggest that the anti-EGFRvIII MAb-CUR-PLGA NPs have potential of targeted drug delivery system for PDT in the overexpressed EGFRvIII tumor cells.

Effects of LED-Based photodynamic therapy using red and blue lights, with natural hydrophobic photosensitizers on human glioma cell line.

Photodynamic therapy (PDT) has received high attention in cancer treatment due to its minimal side effects, specific cancer-targeting, non-invasion and low cost. It utilizes a specific group of anti-cancer drugs called photosensitizers (PS), which can be only activated under a certain wavelength light illumination and kills cancer cells. To screen the potential of PS and setup of PDT treatment protocol, it is essential to assess the PDT efficacy in vitro. In this study, a light-emitting diode- (LED-) based illumination system at two wavelengths (red & blue) with homogeneous and stable irradiation, and constant temperature conditions in 96-well plates was provided. The photodynamic effect of curcumin (CUR) and methyl ester of 5-aminolevulinic acid (MAL) using LED light on human glioma cell line was investigated. The obtained results indicate that this homemade LED-based illumination system is a favorable light source for in vitro PDT in 96-well plates. The PDT using CUR and MAL was efficient at final concentrations of 25µM and 2mM, and light doses of 60J/cm2 and 40J/cm2 respectively. The blue PDT efficiency was dependent on the light and PS doses. MAL-PDT and CUR-PDT using blue LED significantly decreased cell viability in the treatment groups compared with control groups. Furthermore, MAL-PDT using blue LEDs was more effective in comparison with conventional red LEDs on the human glioma cell line.

Fast multislice fluorescence molecular tomography using sparsity-inducing regularization.

Fluorescence molecular tomography (FMT) is a rapidly growing imaging method that facilitates the recovery of small fluorescent targets within biological tissue. The major challenge facing the FMT reconstruction method is the ill-posed nature of the inverse problem. In order to overcome this problem, the acquisition of large FMT datasets and the utilization of a fast FMT reconstruction algorithm with sparsity regularization have been suggested recently. Therefore, the use of a joint L1/total-variation (TV) regularization as a means of solving the ill-posed FMT inverse problem is proposed. A comparative quantified analysis of regularization methods based on L1-norm and TV are performed using simulated datasets, and the results show that the fast composite splitting algorithm regularization method can ensure the accuracy and robustness of the FMT reconstruction. The feasibility of the proposed method is evaluated in an in vivo scenario for the subcutaneous implantation of a fluorescent-dye-filled capillary tube in a mouse, and also using hybrid FMT and x-ray computed tomography data. The results show that the proposed regularization overcomes the difficulties created by the ill-posed inverse problem.