The Prophylactic and Therapeutic Effects of Ficus carica Seed Oil on TNBS-Induced Experimental Model of Ulcerative Colitis

Effect of hydroalcoholic extract of Hibiscus rosa sinensis Linn. leaves in experimental colitis in rats

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is a common, progressive lung condition, characterized by cough and dyspnea and punctuated by episodes of acute exacerbations or “lung attacks” during which these symptoms significantly increase. These lung attacks can induce severe symptoms, causing patients to seek urgent medical care and can result in respiratory failure and death. In the United States, COPD exacerbations are responsible for more than 800 000 hospital admissions each year and 143 000 deaths annually, making it the third leading cause of mortality. Furthermore, acute exacerbations accelerate decline in lung function, reduce patients’ quality of life, and increase health care use (with exacerbation management accounting for up to 70% of the total direct costs of COPD management). Acute exacerbations are common among patients with COPD, with nearly 1 in 2 patients experiencing at least 1 exacerbation annually. Although the pathophysiology of exacerbations is poorly understood, in most cases, it is thought to be provoked by an acute respiratory tract infection (by either a virus or bacteria), which suborns a hyperinflammatory state in the airways, causing patients to experience paroxysms of cough, sputum production, and shortness of breath. Accordingly, these episodes are usually treated with systemic corticosteroids in varying doses and duration. Over the past 30 years, randomized trials have demonstrated the benefits of systemic (usually oral) corticosteroids in providing symptom relief, accelerating lung function recovery, and preventing respiratory failure and treatment relapses in patients experiencing exacerbations. However, prior clinical trials have used different dosing regimens, leading to significant practice variation across physicians, hospitals, and countries. Some trials have used high doses of systemic corticosteroids and tapered the dose over several weeks to months, and others have used fixed (short duration) therapy without any tapering. Currently, there is no firm consensus on the dose or duration of therapy but most national and international guidelines recommend a 10to 14-day course of oral prednisone (approximately40 mg/d). However, even using this conservative regimen, patients frequently experience adverse effects of corticosteroids including hyperglycemia, weight gain, and insomnia. Moreover, because approximately 10% of patients experience frequent exacerbations (defined as 2 or more exacerbations annually), cumulative exposure to oral corticosteroids may be substantial in some patients, leading to serious long-term steroid toxicity, including weight gain, diabetes, osteoporosis, fractures, adrenal suppression, and ocular complications. Because steroid toxicity is dose and duration dependent, ascertainment of a minimal effective dose to treat acute exacerbations is of critical clinical importance for millions of patients with COPD who experience frequent exacerbations. This important but unresolved question is addressed by Leuppi and colleagues in this issue of JAMA. In this rigorous, high-quality, randomized noninferiority clinical trial involving 314 patients with acute exacerbations of COPD, a 5-day course of oral prednisone (at 40 mg daily) was compared with the conventional 14-day course of prednisone as recommended by most guidelines. The study found no significant differences in the primary outcome of treatment relapse (ie, reexacerbation) rate within 180 days (37.2% in the 5-day treatment group vs 38.4% in the 14-day treatment group). There were also no significant differences in lung function or in any of the subjective outcomes such as dyspnea or quality of life between the 2 groups. Thus, the 5-day treatment was noninferior to the 14-day treatment despite a 65% reduction in the cumulative steroid exposure over 6 months in the short-term treatment group (560 mg in the conventional group vs 200 mg median prednisone exposure in the short-term group). While the risk of acute steroid toxicity, including hyperglycemia, was similar between the 2 groups, there were fewer occurrences of hypertension in the short-term treatment group, but this difference was not statistically significant. In addition, patients in the short-term treatment group had significantly shorter hospital stays than those in the con-

Beneficial effect of a novel non-steroidal anti-inflammatory agent with basic character and antioxidant properties on experimental colitis in rats

Comparison of short term and long term multidrug resistant tuberculosis treatment outcomes in tertiary care settings

BackgroundHigh-dose (4.0 g/day) mesalazine is typically used for induction therapy, but its efficacy as maintenance therapy remains to be determined. We conducted a multicenter retrospective study to investigate the efficacy of continuous treatment with 4.0 g/day of mesalazine.Material/MethodsJapanese ulcerative colitis (UC) patients receiving acute induction therapy with 4.0 g/day mesalazine were enrolled and followed. Those who clinically improved or who achieved clinical remission were categorized into 2 sub-groups according to the median duration of treatment with 4.0 g/day of mesalazine. The clinical relapse frequency and the time to relapse were analyzed.ResultsWe enrolled 180 patients with active UC, and then 115 patients who clinically improved or who achieved clinical remission after treatment with 4.0 g/day mesalazine were categorized into 2 sub-groups according to the median of treatment duration: a short-term treatment group (≤105 days, n=58) and a long-term treatment group (>105 days, n=57). Overall, 45 (39.1%) patients relapsed: 28 (48.3%) in the short-term treatment group and 17 (29.8%) in the long-term treatment group. This difference was statistically significant (p<0.05). The relapse-free rate in the long-term treatment group was significantly higher than that in the short-term treatment group (p<0.05). The mean time to relapse in the long-term treatment group was significantly longer than that in the short-term treatment group (425.6±243.8 days vs. 277.4±224.5 days; p<0.05).ConclusionsLong-term continuous treatment with high-dose mesalazine (4.0 g/day) may be more effective than short-term treatment for maintenance of remission in UC patients.

We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.

BackgroundThis study investigated the risk of transurethral resection of prostate (TURP) and acute urine retention (AUR) in relation to 5-alpha-reductase inhibitor (5ARI) therapy.MethodsWe identified 22,687 patients who were newly diagnosed with PE and low urinary tract symptoms (LUTS) between January 1, 2002 and December 31, 2011. We further classified study subjects who had moderate to severe LUTS and a maximum uroflow rate of less than 15ml/sec into three groups by their defined daily dose (DDD) of 5ARI used. The control group consisted of 7–28 cumulative DDD (cDDD) 5ARI users, while the short-term treatment group was 29-179cDDD 5ARI users, and the long-term treatment group was users of more than 180cDDD 5ARI. Each patient was monitored to identify those who subsequently developed TURP and AUR.ResultsTURP and AUR are detected in 5.6% of control group, 7.6% of short-term treatment group and 5.5% of long-term treatment group during 10-year follow up. Compared with the control group, there was no difference in the risk of TURP and AUR in the short-term and long-term treatment groups (HR = 1.41, 95% CI 0.76 to 2.62 and HR = 0.81, 95% CI 0.42 to 1.56, respectively).Conclusion5ARI therapy did not change the risk of TURP and AUR events in patients with PE, moderate to severe LUTS and a maximum uroflow rate of less than 15 ml/sec in 10 years of follow-up. But long-term 5ARI used can postpone AUR and TURP for 8.16 months.

Objective: To evaluate the protective effect of ethanolic extract of dried seeds of Coriandrum sativum L. (C.sativum) in acetic acid-induced ulcerative colitis in rats.Methods: Male Wistar rats were divided into various treatment groups (n=5). The animals were administered with 2ml of acetic acid (4% v/v) via intrarectal route to induce colitis. Prednisolone (2mg/kg) was used as a standard drug and C.sativum was administered at a dose of 100 and 300 mg/kg p.o. Macroscopic scoring, colon weight to length ratio, colonic superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), lipid peroxidation (LPO), myeloperoxidase (MPO) levels and histopathological changes were recorded after the treatment regimen of 11 days.Results: Intrarectal instillation of acetic acid caused significant (P<0.05) increase in colon weight to length ratio, LPO, and MPO levels; and significant (P<0.05) decrease in the levels of SOD, CAT and GSH levels. Pretreatment with C.sativum (100, 300 mg/kg, p.o.) exhibited significant (P<0.05) reversal of all the above biochemical parameters and significantly reversed the histopathological changes induced by acetic acid treatment.Conclusion: The present investigation demonstrates the potent therapeutic value of C.sativum (100, 300 mg/kg, p.o.) in the amelioration of experimental colitis in rats. The beneficial effect of C.sativum could be attributed to its antioxidant effect.

The effect of combining basil seeds and gum Arabic on the healing process of experimental acetic acid-induced ulcerative colitis in rats

In this study, we investigated the effect of melatonin on cisplatin-induced spermiotoxicity using quantitative, biochemical and histopathological approaches. Cisplatin (CP, 7 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected. The rats were decapitated on 5th (short-term group) or 50th day (long-term group) after CP injection. Traits of reproductive organs, sperm characteristics, testicular histological findings, and the lipid peroxidation in the testicular tissue were determined. Melatonin mitigated CP-induced reductions in testes, epididymis and accessory gland weights in rats decapitated on day 5. Both short- and long-term CP treatment decreased sperm concentration, sperm motility and increased abnormal sperm rates compared with the control. But the reduction of sperm concentration in long-term CP treatment was insignificant. Although treatment with melatonin provided moderately normalization with respect to sperm concentration in short-term treatment group, melatonin caused a marked normalization of sperm motility in both CP + melatonin groups. Both groups treated with the melatonin showed decreases in abnormal sperm rates compared with alone CP. While testicular malondialdehyde levels were elevated after CP treatment, glutathione peroxidase activity decreased significantly in both groups. Glutathione levels reduced after long-term treatment, but not in short-term group by CP administration. Treatment with CP plus melatonin provided significant amelioration of oxidative stress parameters. Histopathological findings of testes in both short- and long-term treatment groups paralleled the biochemical and spermatogenic results. This study clearly indicates that CP-treatment impaired markedly testicular function and combined treatment with melatonin prevented much of the toxicity in rats.

Background Intestinal mucosal immune cells, notably mast cells, are pivotal in ulcerative colitis (UC) pathophysiology. Its activation elevates tissue concentrations of histamine. Inhibiting colonic histamine release could be an effective therapeutic strategy for treating UC. Experimental model like 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats mimic human IBD, aiding treatment investigations. Drug repurposing is a promising strategy to explore new indications for established drugs. Desloratadine (DES) is second-generation antihistamine utilized for managing allergies by blocking histamine action in the body. It also has reported anti-inflammatory and antioxidant actions. Objective DES was investigated for its repurposing potential in UC by preclinical screening in TNBS-induced colitis in Wistar rats. Methods Therapeutic efficacy of DES was evaluated both individually and in combination with standard drug 5-aminosalicylicacid (5-ASA). Rats were orally administered DES (10 mg/kg), 5-ASA (25 mg/kg), and DES + 5-ASA (5 mg + 12.15 mg) following the induction of colitis. Parameters including disease activity score rate (DASR), colon/body weight ratio (CBWR), colon length, diameter, pH, histological injury, and scoring were evaluated. Inflammatory biomarkers such as IL-1β, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. Results Significant protective effects of DES, especially in combination with 5-ASA, against TNBS-induced inflammation were observed as evidenced by reduced DASR, CBWR, and improved colon morphology. Drugs significantly lowered plasma and colon histamine and, cytokines levels. GSH restoration, and decreased MDA content were also observed. Conclusion DES and DES + 5-ASA demonstrated potential in alleviating colonic inflammation associated with TNBS-induced colitis in rats. The effect can be attributed to its antihistamine, anticytokine, and antioxidative properties.

Dextran sulfate sodium (DSS)-induced colitis is an experimental model of ulcerative colitis, although the precise mechanism has not yet been elucidated. We investigate whether Zn deficiency affects the pathogenesis of colitis induced by DSS with a focus on immune responses. Male WKAH/Hkm Slc rats were fed either a Zn-adequate (ZA, 30 mg Zn/kg diet) as a control or Zndeficient (ZD, 5 mg Zn/kg diet) diet for 21 days and then treated with 2% DSS via deionized drinking water for 7 days. The disease activity index (DAI) was recorded daily throughout DSS treatment. Serum Zn concentrations were significantly lowered in rats fed the ZD diet than those fed the ZA diet at day 7 and 14. Surprisingly, DSS treatment considerably reduced the serum Zn in both groups. The rats fed the ZD diet showed exacerbated colitis based on clinical outcomes, including weight loss, increased DAI, and shortened colon length. An in vitro study corroborated these results, showing that a large amount of TNFα was induced by rat mesenteric leukocytes in response to lipopolysaccharide in ZD medium, but not in ZA medium. These results indicate that a modulation of TNFα production due to Zn deficiency influences disease activity in DSS-induced colitis. In addition, more attention should be given to Zn for prevention of colitis.

We newly developed a hybrid protein, tentatively named rMIKO-1, using gene technology. We herein investigated the effects of rMIKO-1 on activated macrophages and discussed its potential as a suppressor of experimental colitis. Fluorescent microscopy was used to observe the dynamic mobility of rMIKO-1 in macrophages. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis, Western blotting, fluorescent immunochemical staining, flow cytometry, enzyme-linked immunosorbent assays, a polymerase chain reaction/quantitative polymerase chain reaction, and hematoxylin and eosin staining were conducted to assess the potential activity of rMIKO-1. A large amount of bleeding was observed in rats treated with 5% dextran sulfate sodium (DSS) alone on day 8 after treatment initiation, but not in those treated with 5% DSS plus rMIKO-1. In the in vitro assay, rMIKO-1 rapidly bound to macrophages, immediately entered cells by an unknown mechanism, and then migrated inside the nucleus. This result suggests that rMIKO-1 plays important immunological roles in the nucleus. Despite the activation of macrophages by lipopolysaccharide, the mRNA expression of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, was significantly suppressed in macrophages preliminarily treated with rMIKO-1 for 1 h. Complexes of rMIKO-1 with nuclear factor-kappa B (NF-κB)/p65 and β-actin formed in activated macrophages, which attenuated experimental colitis in rats. These results strongly suggest that rMIKO-1 negatively regulates excessively activated macrophages through the NF-κB/p65 signaling pathway. Therefore, rMIKO-1 is a novel suppressor of experimental colitis in rats through the negative regulation of activated macrophages.

Background: Recent studies have suggested that dietary fiber exerts a therapeutic effect on IBD patients. The aim of this study was to evaluate the effects of a dietary combination of germinated barley foodstuff (GBF), derived from the aleurone and scutellum fraction of germinated barley, plus Clostridium butyricum against dextran sulfate sodium (DSS)-induced experimental colitis in rats. Methods: Sprague-Dawley rats were fed a 3% DSS diet containing GBF only, GBF plus C. butyricum, cellulose only (control) or cellulose plus C. butyricum for 8 days. The mucosal damage (macroscopic and microscopic inflammation) and fecal short-chain fatty acid (SCFA) levels were then determined. Results: The combination of GBF plus C. butyricum most effectively prevented bloody diarrhea and mucosal damage. The GBF-only diet also showed some preventive effects. With respect to fecal SCFAs, the combination of GBF plus C. butyricum most effectively increased the fecal SCFA level. Conclusion: The dietary combination of GBF plus C. butyricum most effectively suppressed DSS-induced experimental colitis in rats. These effects may be closely associated with its high activity to increase SCFA levels in the gut lumen. The potential clinical efficacy of GBF in IBD patients is also discussed.

To determine the effects of heat-killed VSL#3 (B. breve, B. longum and B. infantis; L. plantarum, L. bulgaricus, L. casei and L. acidophilus; S. salivarius subsp. thermophilus) therapy in the dextran sulfate sodium (DSS)-induced acute experimental colitis in rats. Acute experimental colitis was induced in rats by 5% DSS and freely drink for seven days. Beginning on Day 8, rats underwent gavage once daily for seven days with heat-killed probiotic VSL#3 (0.6 g/kg/day), colonic damage was evaluated histologically and biochemically seven days after gavage. Expression of inflammatory related mediators (STAT3, P-STAT3) and cytokines (IL-6, IL-23, TGFβ) in colonic tissue were detected. The results revealed that heat-killed and live VSL#3 have identical anti-inflammatory properties by the assessed DAI (disease activity index), colon length, histological tissue and MPO activity. Heat-killed and live VSL#3 results in reduced IL-6, IL-23, TGFβ, STAT3 and P-STAT3 expression in colonic tissue. Heat-killed and live VSL#3 have showed the similar anti-inflammatory activity by inhibiting IL-6/STAT3 pathway in the DSS-induced acute experimental colitis in rats.