Inhibition of TLR4, NF-κB, and INOS pathways mediates ameliorative effect of syringic acid in experimental ulcerative colitis in rats.

OBJECTIVE: Numerous therapeutics and pharmacological properties have been reported in syringic acid (SA). In this study, we aimed to evaluate effect of SA in ulcerative colitis (UC) in rats considering effect on TLR4, NF-κB, and INOS pathways. MATERIALS AND METHODS: 48 Wistar rats were randomly designated into six groups (n = 8). UC was induced via intra-rectal administration of 7% acetic acid (0.8 ml). SA at doses of 10, 25, 50 mg/kg was administrated through gavage, and dexamethasone (2 mg/kg) administrated intra-peritoneally for 5 consecutive days. The macroscopic and histopathological damages as well as expression of inflammatory and apoptotic genes along with superoxide dismutase (SOD) and catalase (CAT) activities, total antioxidant capacity (TAC), nitric oxide (NO), and malondialdehyde (MDA) levels in the colon tissue were assessed. RESULTS: UC led to an increase in the apoptotic and inflammatory genes, NO and MDA levels as well as decrease in TAC level, and SOD and CAT activities (p < 0.05). UC also caused severe damage, edema, inflammation, and necrosis in the colon. SA significantly reduced gene expressions of INOS, TLR4, IL-6, IL-1ß, NF-κB, Caspase-3, Caspase-8, and Bax. SA ameliorated negative macroscopic and histopathologic effects of UC. SA significantly reduced MDA and NO levels, and increased TAC level and CAT activity in the colon tissue in comparison to the UC rats without treatment (p < 0.05). CONCLUSION: SA via attenuation of the TLR4-NF-κB, NF-κB-INOS-NO pathways, oxidative stress, inflammation, and apoptosis of UC in rats.

Ferulic acid ameliorates ulcerative colitis in a rat model via the inhibition of two LPS-TLR4-NF-κB and NF-κB-INOS-NO signaling pathways and thus alleviating the inflammatory, oxidative and apoptotic conditions in the colon tissue.

INTRODUCTION: Ulcerative colitis is a chronic inflammation of the colon. However, the common treatment for it is accompanied by many complications. Therefore, the present study was aimed to determine the ameliorative effects of ferulic acid on acetic acid-induced colitis in rat. MATERIALS AND METHODS: To induce ulcerative colitis, animals received 0.8 ml of 7% acetic acid intra-rectally. Ferulic acid in 20, 40, and 60 mg/kg doses was administered orally one hour after the ulcerative colitis induction. Animals received treatments for five consecutive days and then were euthanized on the sixth day. The colon was dissected out and macroscopic lesions were examined. Colon samples were evaluated for histopathological examination, biochemical analysis, determination of the expression of inflammatory, and apoptotic genes as well as total antioxidant capacity. RESULTS: Ferulic acid significantly inhibited inflammatory and apoptotic genes mRNA expression, also production of MDA and NO. Ferulic acid significantly increased the activity of antioxidant factors (TAC content, and SOD and CAT activity), thereby preventing inflammation and histopathological damage in the colon tissue of colitis rats. CONCLUSION: The results of the present study confirmed the antioxidant, anti-inflammatory, and anti-apoptotic properties of ferulic acid. About the mechanism of action of this compound, it can be concluded that the ability of ferulic acid in the amelioration of ulcerative colitis is related to the inhibition of two LPS-TLR4-NF-κB and NF-κB-INOS-NO signaling pathways.

The coumaric acid and syringic acid ameliorate acetic acid-induced ulcerative colitis in rats via modulator of Nrf2/HO-1 and pro-inflammatory cytokines.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes uncontrolled inflammation and ulcers in your digestive tract. The coumaric acid and syringic acid are phenolic derivative found in many fruits and vegetables and is widely recognized for the ability of anti-parasitic, anti-microbial, anti-viral, anti-inflammatory, and antioxidant. The purpose of this study was to investigate the anti-inflammatory and antioxidant properties of coumaric acid and syringic acid on acetic acid-induced colitis in rats. METHODS: A total of 64 male Wistar rats were divided into eight equal groups (n = 8). Colitis was induced by intrarectal administration of acetic acid, and rats orally received coumaric acid (100 and 150 mg/kg), syringic acid (10, 25, and 50 mg/kg), and dexamethasone (2 mg/kg) once per day for four days after colitis induction. Then, HO-1, Nrf2, and NQO1 mRNA expression were quantified by real time-PCR. Finally, the tissue levels of TNF-α and IL-1ß protein were measured by ELISA. RESULTS: Colitis led to a decrease in HO-1, Nrf2, and NQO1 mRNA expression and an increase in the tissue levels of TNF-α and IL-1ß protein in the colon tissue. Treatment with dexamethasone significantly increased HO-1, Nrf2, and NQO1 mRNA expression and decreased the tissue levels of TNF-α and IL-1ß protein compared to the UC group. Treatment with 150 mg/kg of coumaric acid and 50 mg/kg of syringic acid significantly increased HO-1, Nrf2, and NQO1 mRNA expression compared to the UC group. Also, treatment with 100 and 150 mg/kg of coumaric acid and 10, 25, and 50 mg/kg of syringic acid significantly decreased the tissue levels of TNF-α and IL-1ß protein compared to the UC group. CONCLUSION: The coumaric acid and syringic acid, especially at high doses, may be an alternative strategy for the treatment of UC by the reduction of TNF-α and IL-1ß levels and upregulation of the Nrf2/HO-1 pathway.

In silico design of a multi-epitope vaccine against HPV16/18.

BACKGROUND: Cervical cancer is the fourth most common cancer affecting women and is caused by human Papillomavirus (HPV) infections that are sexually transmitted. There are currently commercially available prophylactic vaccines that have been shown to protect vaccinated individuals against HPV infections, however, these vaccines have no therapeutic effects for those who are previously infected with the virus. The current study's aim was to use immunoinformatics to develop a multi-epitope vaccine with therapeutic potential against cervical cancer. RESULTS: In this study, T-cell epitopes from E5 and E7 proteins of HPV16/18 were predicted. These epitopes were evaluated and chosen based on their antigenicity, allergenicity, toxicity, and induction of IFN-γ production (only in helper T lymphocytes). Then, the selected epitopes were sequentially linked by appropriate linkers. In addition, a C-terminal fragment of Mycobacterium tuberculosis heat shock protein 70 (HSP70) was used as an adjuvant for the vaccine construct. The physicochemical parameters of the vaccine construct were acceptable. Furthermore, the vaccine was soluble, highly antigenic, and non-allergenic. The vaccine's 3D model was predicted, and the structural improvement after refinement was confirmed using the Ramachandran plot and ProSA-web. The vaccine's B-cell epitopes were predicted. Molecular docking analysis showed that the vaccine's refined 3D model had a strong interaction with the Toll-like receptor 4. The structural stability of the vaccine construct was confirmed by molecular dynamics simulation. Codon adaptation was performed in order to achieve efficient vaccine expression in Escherichia coli strain K12 (E. coli). Subsequently, in silico cloning of the multi-epitope vaccine was conducted into pET-28a ( +) expression vector. CONCLUSIONS: According to the results of bioinformatics analyses, the multi-epitope vaccine is structurally stable, as well as a non-allergic and non-toxic antigen. However, in vitro and in vivo studies are needed to validate the vaccine's efficacy and safety. If satisfactory results are obtained from in vitro and in vivo studies, the vaccine designed in this study may be effective as a therapeutic vaccine against cervical cancer.

Design of a multi-epitope vaccine against cervical cancer using immunoinformatics approaches.

Cervical cancer, caused by human papillomavirus (HPV), is the fourth most common type of cancer among women worldwide. While HPV prophylactic vaccines are available, they have no therapeutic effects and do not clear up existing infections. This study aims to design a therapeutic vaccine against cervical cancer using reverse vaccinology. In this study, the E6 and E7 oncoproteins from HPV16 were chosen as the target antigens for epitope prediction. Cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) epitopes were predicted, and the best epitopes were selected based on antigenicity, allergenicity, and toxicity. The final vaccine construct was composed of the selected epitopes, along with the appropriate adjuvant and linkers. The multi-epitope vaccine was evaluated in terms of physicochemical properties, antigenicity, and allergenicity. The tertiary structure of the vaccine construct was predicted. Furthermore, several analyses were also carried out, including molecular docking, molecular dynamics (MD) simulation, and in silico cloning of the vaccine construct. The results showed that the final proposed vaccine could be considered an effective therapeutic vaccine for HPV; however, in vitro and in vivo experiments are required to validate the efficacy of this vaccine candidate.