Short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber contribute a significant proportion of daily energy requirement. Furthermore, these compounds are modulators of macrophage function and potential targets for the development of new drugs. The aims of this study were to evaluate the effects of three types of SCFAs (sodium acetate (NaAc), sodium propionate (NaP), and sodium butyrate (NaB)) on the production of NO and inducible nitric oxide synthase (iNOS) and proinflammatory and antiinflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin (IL-1, IL-6, and IL-10)) and to observe the effect of NaAc on inhibiting lipopolysaccharide (LPS)-induced NF-κB activation in LPS-stimulated RAW264.7 cells. The results show that three types of SCFAs (acetate, propionate, and butyrate) reduced the production of proinflammatory factors, including TNF-α, IL-1β, IL-6, and NO, and inhibited the vitality of iNOS. Meanwhile, SCFAs enhanced the production of antiinflammatory cytokine IL-10 in lower concentrations (1-1,200 μmol/L). Like NaB, NaAC inhibited LPS-induced NF-κB activation. These results may hold promise on the role that SCFAs have on the prevention and treatment of various inflammatory conditions.

OBJECTIVES ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur most frequently in ovarian clear cell and endometrioid carcinomas and uterine endometrioid carcinomas. Since endometriosis is thought to be a precursor of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma). MATERIALS/METHODS Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 and mixed clear cell and endometrioid carcinoma in 3. RESULTS ARID1A loss was observed in 31 (66%) of 47 carcinomas and therefore these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma and thus these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor. CONCLUSIONS The findings in this study provide cogent evidence that loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event, occurring before malignant transformation, in the development of the majority of ovarian clear cell and endometrioid carcinomas arising in endometriomas.

Abbreviations used in this paper: BrdU, bromodeoxyuridine; CDS, coding sequence; CP, cortical plate; DCX, doublecortin; E, embryonic day; IZ, intermediate zone; p-H3 + , phospho -Histone H3 + ; RGS, Regulator of G protein Signaling; shRNA, short hairpin RNA; SVZ, subventricular zone; VZ, ventricular zone.The online version of this paper contains supplemental material.

ARID1A is a recently identified tumor suppressor that functions in chromatin remodeling. Inactivating mutations of ARID1A and loss of its expression most frequently occur in ovarian clear cell carcinoma, ovarian endometrioid carcinoma, and uterine endometrioid carcinoma. In this study, we performed a detailed immunostaining analysis of ARID1A in 246 cases including benign endometrium and endometrioid carcinoma at different stages of progression. Special attention was paid to recording intratumoral heterogeneity of clonal loss of ARID1A immunoreactivity. All normal endometria (n= 51) and endometrial polyps (n= 14) retained ARID1A expression. Among complex atypical hyperplasia (n= 38), 16% exhibited clonal loss of ARID1A, but none showed complete loss. Among low-grade endometrioid carcinomas (n= 88), 25% exhibited complete loss and 24% exhibited clonal loss. In contrast, 44% of high-grade endometrioid carcinomas (n= 55) showed complete loss of ARID1A and 9% exhibited clonal loss. We found that 19 high-grade carcinomas also contained concurrent low-grade carcinomas. In the high-grade areas, 63% exhibited complete loss and 11% exhibited clonal loss, whereas in the low-grade areas, 37% exhibited complete loss and 42% clonal loss. In 5 of these 19 cases, progressive loss of ARID1A from retention or clonal loss to complete loss was observed between the low-grade and high-grade areas. Overall, the percentage of complete ARID1A loss increased from 0% in complex atypical hyperplasia, to 25% in low-grade endometrioid carcinoma, to 44% in high-grade endometrioid carcinoma. These findings suggest that loss of ARID1A expression, presumably due to mutation, plays an important role in tumor progression of uterine endometrioid carcinoma.