Nicotine interacts with DNA lesions induced by alpha radiation which may contribute to erroneous repair in human lung epithelial cells.

PURPOSE: Epidemiological studies show that radon and cigarette smoke interact in inducing lung cancer, but the contribution of nicotine in response to alpha radiation emitted by radon is not well understood. MATERIALS AND METHODS: Bronchial epithelial BEAS-2B cells were either pre-treated with 2 µM nicotine during 16 h, exposed to radiation, or the combination. DNA damage, cellular and chromosomal alterations, oxidative stress as well as inflammatory responses were assessed to investigate the role of nicotine in modulating responses. RESULTS: Less γH2AX foci were detected at 1 h after alpha radiation exposure (1-2 Gy) in the combination group versus alpha radiation alone, whereas nicotine alone had no effect. Comet assay showed less DNA breaks already just after combined exposure, supported by reduced p-ATM, p-DNA-PK, p-p53 and RAD51 at 1 h, compared to alpha radiation alone. Yet the frequency of translocations was higher in the combination group at 27 h after irradiation. Although nicotine did not alter G2 arrest at 24 h, it assisted in cell cycle progression at 48 h post radiation. A slightly faster recovery was indicated in the combination group based on cell viability kinetics and viable cell counts, and significantly using colony formation assay. Pan-histone acetyl transferase inhibition using PU139 blocked the reduction in p-p53 and γH2AX activation, suggesting a role for nicotine-induced histone acetylation in enabling rapid DNA repair. Nicotine had a modest effect on reactive oxygen species induction, but tended to increase alpha particle-induced pro-inflammatory IL-6 and IL-1ß (4 Gy). Interestingly, nicotine did not alter gamma radiation-induced γH2AX foci. CONCLUSIONS: This study provides evidence that nicotine modulates alpha-radiation response by causing a faster but more error-prone repair, as well as rapid recovery, which may allow expansion of cells with genomic instabilities. These results hold implications for estimating radiation risk among nicotine users.

A Study on Association Between Protein Carbonyl and Anti-cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis: Introducing a New Supplementary Biomarker.

Redox state and immune mechanisms are two major factors implicated in rheumatoid arthritis (RA). Regarding some limitations of anti-cyclic citrullinated peptide (anti-CCP) antibody in RA diagnosis, recruiting another strong marker of oxidative stress could lead to more definitive diagnosis. To evaluate the potential of protein carbonyl content as a supplementary biomarker for RA. Eighty patients with RA attending the Research Center from 2015 to 2016 were recruited in this study. Smoker and alcoholic subjects, or those with any other systemic illness were excluded from the study. Demographic information and clinical data were collected. Numbers of swollen and tender joints were determined and RA disease activity was assessed. Serum samples were used for assessing protein carbonyl level, platelet count, and anti-CCP antibody values. Statistical analyses for significant differences were performed according to parametric (Student t test) and nonparametric (Mann-Whitney test) tests. The correlation was determined by Pearson coefficient. There was a significant correlation between protein carbonyl levels and anti-CCP antibodies in active RA (p value = 0.01), but not in remission phase (p value = 0.28). A significant positive correlation was observed between protein carbonyl levels and platelets count in active RA (p value = 0.001), but not in remission phase (p value = 0.85). Protein carbonyl could be considered as a future cost-effective supplementary biomarker, alongside anti-CCP antibody, in active RA diagnosis as it showed a significant positive correlation with anti-CCP antibody and platelet, two major mediators in the disease pathogenesis.

Anti-Hypolipidemic and Anti-Oxidative Effects of Hydroalcoholic Extract of Origanum majorana on the Hepatosteatosis Induced with High-Fat Diet in Rats.

INTRODUCTION: The aim of the current study is to evaluate the antihyperlipidemic and anti-oxidative effects of hydro-alcoholic extract of marjoram (HAEM) in rats fed with a high-fat diet (HFD). METHODS: In the experimental study, the rats were randomly divided into four groups of five rats in each and fed with high-fat diet for 12 weeks as follows: One group (normal diet group) was fed with a standard diet, one group was fed with HFD, and two groups were fed with HFD and orally fed with 150 and 450 mg/kg/day HAEM. The serum samples and liver tissues were used for measuring the biochemical and oxidative parameters and histopathological studies. HFD induced hepatosteatosis in rats as evidenced by the altered liver enzymes activity, serum lipid profile and oxidative status. RESULTS: Serum lipid profile (triglyceride, cholesterol and low-density lipoprotein) in rats fed with HFD + HAEM (150 and 450 mg/kg/day) was significantly decreased. Furthermore, the evaluation of oxidative stress showed a reduction of the malondialdehyde (MDA) level and an increase in ferric-reducing anti-oxidant power. Meanwhile, liver enzyme activities declined in response to HAEM. CONCLUSION: Using the HAEM could be a future therapeutic agent in treating hepatosteatosis and reducing oxidative damages of HFD in the liver.

The immunomodulatory effects of tachykinins and their receptors.

Tachykinins (TKs) are a family of neuropeptides mainly expressed by neuronal and non-neuronal cell types, especially immune cells. Expression of TKs receptors on immune cell surfaces, their involvement in immune-related disorders, and therefore, understanding their immunomodulatory roles have become of particular interest to researchers. In fact, the precise understanding of TKs intervention in the immune system would help to design novel therapeutic approaches for patients suffering from immune disorders. The present review summarizes studies on TKs function as modulators of the immune system by reviewing their roles in generation, activation, development, and migration of immune cells. Also, it discusses TKs involvement in three main cellular mechanisms including inflammation, apoptosis, and proliferation.

Clinical Trial Assessment of Intermittent and Continuous Infusion Dose of N-Acetylcysteine on Redox Status of the Body in Patients with Sepsis Admitted to the ICU.

PURPOSE: Conflicting results exist regarding the efficacy of N-acetyl cysteine (NAC) in sepsis treatment. A pivotal factor affecting the therapeutic potency of NAC in sepsis is timing and dosing of its infusion. We aimed to assess the effect of NAC on redox status of patients with sepsis and to compare its efficacy in intermittent and continuous infusion with the objective of developing the infusion regimen and optimizing the timing. MATERIALS AND METHODS: A prospective, randomized clinical trial was designed to compare the antioxidative effect of NAC in intermittent infusion group (IV: 25 mg/kg bolus and then 25 mg/kg/8 hours 3 times) and continuous infusion group (IV: 25 mg/kg bolus and then 75 mg/kg over 24 hours) in 60 critically ill patients with sepsis (20 patients in each group). Blood samples were collected immediately before and after intervention for total antioxidant capacity (TAC) and malondialdehyde (MDA) assessment. RESULTS: N-acetyl cysteine considerably increased TAC levels in both intermittent (0.68 ± 0.60; P value = .036) and continuous (0.69 ± 0.64; P value = .015) infusion groups when compared to placebo (0.61 ± 0.10); however, the difference in TAC levels between the intermittent and the continuous infusion did not reach statistical significance (P value = .942). Likewise, NAC treatment decreased MDA levels in both intermittent (19.45 ± 4.18; P value = 0.001) and continuous (22.47 ± 6.68; P value = .002) infusion groups when compared to placebo (31.76 ± 11.06), while the difference in MDA levels between the intermittent and the continuous infusion did not reach statistical significance (P value = .481). CONCLUSION: Our data confirmed the antioxidative effect of NAC treatment in patients with sepsis, with no significant difference in intermittent and continuous infusion.

Novelty in limbal stem cell culture and cell senescence.

Limbal stem cell deficiency is a pathological state. Recently, limbal stem cell (LSC) transplantation has attracted great interest as a therapeutic method which mainly involves in-vitro expansion of LSCs. It is believed that ex-vivo cultivation conditions could affect the outcome of surgery and the rate of successful transplantation. Thus, we aimed to define a suitable culture condition by conducting a research on ex-vivo expanded LSCs to maintain an optimized graft of amniotic membrane with cultivated-limbal stem cells, regarding the quantity and quality, with the hope of improving the clinical outcome.

Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in breast cancer.

Breast cancer is the second leading cause of cancer death in women with increasing incidence. Hence, finding a diagnostic factor and/or potential drug target could lead to an earlier diagnosis or a more effective therapeutic protocol. It is shown that substance P (SP) through its receptor neurokinin-1 (NK1R) could initiate tumor cell proliferation, angiogenesis, and migration. This was a case-control study on 41 women with breast cancer and 34 healthy controls. Serum level of SP was measured using an ELISA method, and immunohistochemistry staining was performed to study NK1R expression in different cell compartments. Assessing serum SP values of patients showed significantly higher levels than those of healthy individuals. However, no significant correlation was found between SP levels and tumor criteria, but between SP and HER-2. Moreover, the percentage, intensity of staining as well as tissue distribution of NK1R were significantly higher in tumor tissues as compared with controls. Increased serum SP levels and NK1R tissue distribution were observed in patients with breast cancer as compared with their controls, highlighting the involvement of SP/NK1R complex in breast cancer incidence. NK1R profound expression in tumor cell cytoplasm and its significant correlation with the majority of cancer features can be of importance to be taken into consideration as a possible potential therapeutic target in future targeted therapeutic strategies. Furthermore, cytoplasmic expression of NK1R can be suggested as a potent prognostic factor as it has shown significant correlation with TNM and tumor grade.

Herbal medicine in oral lichen planus.

Oral lichen planus (OLP) is a common chronic inflammatory and T cell-mediated autoimmune disease in which the oral mucosa, tongue, and gingiva are involved. Different treatments have been suggested to reduce the symptoms of this disease. Currently, a common treatment for OLP is the use of corticosteroids as the gold standard, although they have considerable side effects. The chronicity of the disease needs the long-term use of these drugs with ensuing side effects. Therefore, various studies have been done to find an alternative and effective treatment. The use of herbal medicine as an alternative therapy with antioxidant and anti-inflammatory properties seems promising. Hence, this review study was done to summarize the efficiency of different herbal medicine in the treatment of OLP.

Crocin synergistically enhances the antiproliferative activity of 5-flurouracil through Wnt/PI3K pathway in a mouse model of colitis-associated colorectal cancer.

Colorectal cancer (CRC) is the third most common cause of cancer-related death, and hence there is a need for the identification of novel-agents to improve the efficacy of existing therapies. There is growing evidence for the antitumor activity of crocin, although its activity and molecular mechanisms in CRC remains to be elucidated. Here we explored the therapeutic application of crocin or its combination with 5-flurouracil in a mouse model of colitis-associated colon cancer. The antiproliferative activity of crocin was assessed in two-dimensional and three-dimensional cell-culture models. The migratory behaviors were determined, while the expression levels of several genes were assessed by quantitative reverse transcriptase polymerase chain reaction/Western blot analysis. We examined the anti-inflammatory properties of crocin by pathological evaluation and disease-activity index as well as oxidative or antioxidant markers: malondialdehyde (MDA) and total-thiols (T-SH) levels and superoxide dismutase (SOD) and catalase (CAT) activity. Crocin suppressed cell-growth and the invasive behavior of CRC cells through modulation of the Wnt-pathway and E-cadherin. Moreover, administration of crocin alone, or in combination with 5-FU dramatically reduced the tumor number and tumor size in both distal/mid-colon followed by reduction in disease-activity index. Crocin also suppressed the colonic inflammation induced by dextran-sulfate-sodium and notably recovered the increased levels of MDA, decreased thiol levels and activity of CAT levels. Crocin was able to ameliorate the severe inflammation with mucosal ulcers and high-grade dysplastic crypts as detected by inflammation score, crypt loss, pathological changes and histology scores. We demonstrated an antitumor activity of crocin in CRC and its potential role in improvement of inflammation with mucosal ulcers and high-grade dysplastic crypts, supporting the desireability of further investigations on the therapeutic potential of this approach in CRC.

Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status, and perspectives.

Mammalian target of rapamycin (mTOR) signaling pathway controls cell energy metabolism. There is an interplay between mTOR and proinflammatory signaling pathways, supporting the role of the pathway in the pathogenesis of inflammatory diseases. Inhibition of mTOR signaling using specific pharmacological inhibitors could offer therapeutic promise in several inflammatory-associated diseases. In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis, and rheumatoid arthritis for a better understanding and hence a better management of these diseases.

Therapeutic potency of heat-shock protein-90 pharmacological inhibitors in the treatment of gastrointestinal cancer, current status and perspectives.

OBJECTIVES: Heat-shock protein-90 (HSP90) chaperone machinery is critical to the folding, stability and activity of several client proteins including many responsible for tumour initiation, progression and metastasis. Overexpression of HSP90 is correlated with poor prognosis of GI cancer. KEY FINDINGS: Pharmacological inhibitors of HSP90 suppress tumorigenic effects of HSP90 by suppressing angiogenesis, survival, metastasis and drug resistance in GI cancer. This review summarizes the role of HSP90 inhibitors in the treatment of GI cancer. SUMMARY: We have presented different antitumour mechanisms of HSP90 inhibitors in cancer treatment. Suppression of HSP90 signalling via specific and novel pharmacological inhibitors is a potentially novel therapeutic approach for patients with GI cancer for a better understanding and hence a better management of this disease.