薏苡附子败酱散联合电针治疗对AOM/DSS小鼠炎症相关性结直肠癌的防治作用及机制

目的:探究薏苡附子败酱散(Yiyi Fuzi Baijiang San,YYFZBJS)联合电针(electroacupuncture,EA)对AOM/DSS模型小鼠炎症相关性结直肠癌（colitis-associated colorectal cancer,CAC）的防治作用及对结直肠癌上皮间质转化（epithelial-mesenchymal transition,EMT）相关蛋白表达情况的影响。方法:建立AOM/DSS诱导的CAC小鼠模型,将40只小鼠随机分为模型组、针药结合组、薏苡附子败酱散组、电针组和阿司匹林组,于实验第2周开始干预治疗,治疗过程中记录各组小鼠一般情况,统计体质量变化、疾病活动指数（disease activity index,DAI）评分及生存情况,于实验末比较各组小鼠结直肠长度、成瘤数量及肿瘤大小,通过HE染色观察结直肠组织及肿瘤组织的病理变化,免疫组织化学染色观察结直肠肿瘤Ki-67、PCNA、p-NF-κB、NF-κB、E-cadherin、ZO-1、Occludin、Vimentin和N-cadherin蛋白的表达。结果:与模型组相比,针药结合组小鼠体质量显著升高(P＜0.05),DAI分值降低(P＜0.05),生存率为87.5%,结直肠长度显著增加（P＜0.01）,直径小于2 mm的肿瘤数量减少(P＜0.05),直径介于2~4 mm之间和大于4 mm的肿瘤数量显著减少（P＜0.01）,总成瘤数量明显下降（P＜0.01）,结直肠形态明显改善;肿瘤组织病理评分降低（P＜0.01）,肿瘤组织中Ki-67、PCNA、p-NF-κB、NF-κB、Vimentin和N-cadherin蛋白表达量降低（P＜0.01）,E-cadherin、ZO-1和Occludin蛋白表达量升高(P＜0.05)。结论:薏苡附子败酱散联合电针对AOM/DSS模型小鼠的CAC发生发展有防治作用,其机制可能与下调NF-κB信号通路,减缓EMT进程有关。     

Selectively targeting estrogen receptors for cancer treatment

Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ERα and ERβ, which mediate proliferation and differentiation of cells. For decades, ERα mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most notably with the selective estrogen receptor modulator (SERM) tamoxifen. Selectively targeting ERs occurs at two levels: tissue selectivity and receptor subtype selectivity. SERMs have been developed with emphasis on tissue selectivity to target ER signaling for breast cancer treatment. Additionally, new approaches to selectively target the action of ERα going beyond ligand-dependent activity are under current investigation. As evidence of the anti-proliferative role of ERβ accumulates, selectively targeting ERβ is an attractive approach for designing new cancer therapies with the emphasis shifted to designing ligands with subtype selectivity. This review will present the mechanistic and structural features of ERs that determine tissue and subtype selectivity with an emphasis on current approaches to selectively target ERα and ERβ for cancer treatment.     

PPARα contributes to colonic protection in mice with DSS-induced colitis

Inflammatory bowel disease (IBD) is characterized by repeated chronic inflammation of the gastrointestinal tract. We have used the complementary model of colonic inflammation to examine the roles of peroxisome proliferator-activated receptor α (PPARα) in colonic inflammation and thus its possible role in IBD. We characterized an innate immune-mediated model of colitis induced by dextran sulfate sodium (DSS). Mice with DSS-induced colitis were injected with Wy-14643 (2 mg/kg) as a PPARα agonist every day from day 0 to day 5. We show that mice given Wy-14643 were less susceptible to experimental acute colitis induced by DSS, and this decreased susceptibility was correlated with decreased production of IFNγ, IL-1β, IL-6, and TNF-α. Our findings suggest that PPARα has a role in controlling colonic inflammation and mucosal tissue homeostasis.     

Physical and chemical insults induce inflammation and gastrointestinal cancers

Chronic inflammation associated with viral and bacterial infections of the gastrointestinal tract (GI) and liver renders these organs susceptible to tumour development. There is also a growing body of evidence demonstrating that chemical and physical insults promote GI cancers by inducing inflammation. For example, excessive alcohol consumption and tobacco smoking induces inflammation and gastrointestinal carcinogenesis. Likewise, drinking hot beverages and intentional or accidental exposure to toxic substances leads to inflammation and GI cancer formation. However, further work needs to be undertaken using animal models to separate the direct carcinogenic effects of physical and chemical insults from the indirect effects of these insults to promote tumor formation through tissue inflammation.     

Human filarial proteins attenuate chronic colitis in an experimental mouse model

Encouraged by our earlier results of promising therapeutic effect of filarial recombinant proteins BmALT2, BmCys and WbL2 individually in the mouse model of acute ulcerative colitis, in this study, these proteins have been explored individually and in different combinations for their therapeutic potential in dextran sulphate sodium (DSS)‐induced chronic colitis mice. These mice, treated with filarial proteins, showed reduced disease parameters including body weight loss, disease activity index, macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Among various treatment schemes, rBmALT2 + rBmCys which showed most pronounced therapeutic implication was found to downregulate the mRNA expressions of IFN‐γ and TNF‐α and upregulate IL‐10 and TGF‐β expression in the splenocytes. Also, increase in level of IgG1 and IgG2a isotypes in the sera of rBmALT2 + rBmCys‐treated colitis mice was noted. Activated NF‐κB level was found to be reduced in the colon of treated colitis mice compared to untreated one. In conclusion, filarial proteins in combination have been shown to improve the clinicopathologic status of chronic colitis through suppression of pro‐inflammatory immune response most possibly in NF‐κB‐dependent manner. We propose this therapeutic strategy to be tested further to be considered as an effective option in chronic colitis.     

Birth characteristics and acute otitis media in early life

Objective

To assess whether preterm birth and low birth weight were associated with single and recurrent episodes of acute otitis media (AOM) the first 18 months of life.

Methods

The study population consisted of 33,192 children in the Norwegian Mother and Child Cohort, conducted at the Norwegian Institute of Public Health. The majority of all pregnant women in Norway were invited to participate and the response rate was 44%. Participating women received questionnaires during pregnancy and when the child was 6 and 18 months. Main outcome measures were maternal reports of AOM at ages 6, 11 and 18 months. Information on birth weight and gestational age was obtained from the Medical Birth Registry of Norway. Regression analyses were performed controlling for a variety of potential confounders.

Results

Preterm birth was slightly associated with both single and recurrent episodes of AOM the first 18 months of age. The adjusted relative risk (aRR) for having any episode of AOM was 1.37, 95%CI (1.12-1.68) if born before week 33, and the aRR for having recurrent AOM was 1.34, 95%CI (1.01-1.77) if born in weeks 33-36 (reference group: ≥37 weeks). A corresponding tendency was not found for low birth weight.

Conclusions

The finding indicates a modest increased risk of having AOM in children born preterm, and preterm birth seems to be more important than low birth weight in determining risk of having AOM in early life.     

Substance P and vasoactive intestinal peptide levels in middle ear effusions of children

Abstract Conclusion: This is the first report demonstrating high levels of substance P (SP) that inversely correlate with vasoactive intestinal peptide (VIP) levels in middle ear effusions (MEEs) of patients with otitis media with effusion (OME). Increased SP and decreased VIP levels might play a role in the pathogenesis of chronic OME. Objective: The etiology of OME is multifactorial, and neurogenic inflammation may play a significant role. SP and VIP levels were not evaluated previously in MEEs of children with OME. Methods: Fifty patients aged 2-12 years (mean age 5.24 ± 2.64) were included in the study. MEEs were classified as mucoid or serous based on the gross appearance. SP and VIP levels were determined using ELISA. Results: High levels of SP were detected in MEEs. In addition SP levels were significantly higher in serous samples (2910.55 ± 307.96 vs 2218.55 ± 262.30 pg/ml). There were also age-dependent changes, such that SP levels were significantly higher in children aged 2-3 years compared with those who were 4-5 and 6-12 years old. VIP levels were undetectable in 30% of patients and the mean level of VIP was 50.91 ± 16.01 pg/ml in serous middle ear effusions and 54.86 ± 15.91 pg/ml in mucoid MEEs.     

Acute otitis media in schoolchildren: allergic diseases and skin prick test positivity

Conclusions. Single and repeated episodes of acute otitis media (AOM) in 10-year-old children were associated with reported allergic disease. Further, skin prick test (SPT)-negative children with reported asthma and allergic rhinoconjunctivitis had increased risk of AOM. We suggest that optimal treatment of allergic symptoms may have an effect on AOM in school children. Objective. The objective of the study was to estimate associations between AOM, allergic diseases and SPT positivity in 10-year-old children. Materials and methods. Population-based cross-sectional study of 3406 10-year-old children living in Oslo. Main outcome measures were questionnaire-based information on AOM and reported physician-diagnosed allergic diseases with symptoms during the last year. In addition, 2657 children were skin prick tested. Logistic regression analyses were performed to estimate associations and control for potential confounders. Results. One or more episodes of AOM were present in 13.8% (n=470) of the children; 9.7% (n=331) had single episodes, while 4.1% (n=139) had two or more infections. We found a statistically significant association between AOM and reported allergic diseases, strongest for AOM and asthma with odds ratio 2.7 (95% confidence interval 1.8–4.0) and 2.3 (95% confidence interval 1.3–4.3) for single and two or more episodes of AOM, respectively. The risk for AOM was increased in asthmatic SPT-negative children compared with asthmatic SPT-positive children, the odds ratios were 3.0 (1.7–5.4) and 1.5 (0.8–2.8), respectively. The same tendency was found for allergic rhinoconjunctivitis.