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.

Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

Diabetes is accompanied by several complications. Higher prevalence of cancers, cardiovascular diseases, chronic kidney disease (CKD), obesity, osteoporosis, and neurodegenerative diseases has been reported among patients with diabetes. Metformin is the oldest oral antidiabetic drug and can improve coexisting complications of diabetes. Clinical trials and observational studies uncovered that metformin can remarkably prevent or alleviate cardiovascular diseases, obesity, polycystic ovarian syndrome (PCOS), osteoporosis, cancer, periodontitis, neuronal damage and neurodegenerative diseases, inflammation, inflammatory bowel disease (IBD), tuberculosis, and COVID-19. In addition, metformin has been proposed as an antiaging agent. Numerous mechanisms were shown to be involved in the protective effects of metformin. Metformin activates the LKB1/AMPK pathway to interact with several intracellular signaling pathways and molecular mechanisms. The drug modifies the biologic function of NF-κB, PI3K/AKT/mTOR, SIRT1/PGC-1α, NLRP3, ERK, P38 MAPK, Wnt/ß-catenin, Nrf2, JNK, and other major molecules in the intracellular signaling network. It also regulates the expression of noncoding RNAs. Thereby, metformin can regulate metabolism, growth, proliferation, inflammation, tumorigenesis, and senescence. Additionally, metformin modulates immune response, autophagy, mitophagy, endoplasmic reticulum (ER) stress, and apoptosis and exerts epigenetic effects. Furthermore, metformin protects against oxidative stress and genomic instability, preserves telomere length, and prevents stem cell exhaustion. In this review, the protective effects of metformin on each disease will be discussed using the results of recent meta-analyses, clinical trials, and observational studies. Thereafter, it will be meticulously explained how metformin reprograms intracellular signaling pathways and alters molecular and cellular interactions to modify the clinical presentations of several diseases.

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.