Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice

Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17β-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment.

Elastography of Endometrium in Women Taking Tamoxifen: A New Approach to an Old Diagnostic Problem

Tamoxifen is a commonly used selective estrogen receptor modulator applied in the treatment for breast cancer. However, in the endometrium, Tamoxifen stimulates tissue growth, cellular transformation, the migration of the cells, and metastatic potential in endometrial cancer. Considering that uterine cancer is the most common neoplasm of the reproductive tract and the third most common neoplastic disease in women, the aim of this study was to investigate if applying elastography in examining the endometrium was beneficial for uterine cancer screening protocols in women on selective estrogen receptor modulator therapy. This study was based on the execution of a classic assessment of the endometrium that included the evaluation of the following: echogenicity, central endometrial stripe, presence of fluid in the uterine lumen, myometrium–endometrium interface, intensity of vascularization and vascular pattern. An ultrasound presentation was then processed and analyzed with elastography. The values of the elastography parameters demonstrated good consistency for the measurement of the softest endometrial layer thickness in elastography. A strong positive correlation (R = 0.56) was demonstrated between the endometrial thickness, as determined by ultrasound examination, and the softest endometrial layer in elastography (p < 0.001). The research showed that the elastography measurements of the width of the softest endometrium layer, based on a population of women taking Tamoxifen, appeared to be a promising option for endometrial cancer screening.

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of typical symptoms associated with ischemia but are linked to cognitive decline and the development of dementia. There are no approved treatments for SI, but one potential treatment is tamoxifen, a selective estrogen receptor modulator. While SI can have long-term consequences, it is critical to establish whether treatments are able to selectively target its early consequences, to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 hours later against cognitive deficits and injury responses to SI including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). Hippocampal SI led to subtle cognitive impairment on the object place recognition task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but did increase apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI also increased ERα and decreased ERβ in the hippocampus, which was again mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that the SI rats given tamoxifen were indistinguishable from sham controls. Further, SI rats were significantly different from all other groups, an effect produced by low levels of ERα and increased apoptosis, gliosis, inflammation, ERβ, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI as early as 24 hours after injury. This effect is driven by mitigation of apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

The effect of a selective estrogen receptor modulator – raloxifene – on the levels of tryptophan and kynurenic acid in the livers of rats as studied via RP-HPLC-FL

The levels of tryptophan (TRP) and its main metabolite kynurenic acid (KYNA) were measured in rat livers treated with raloxifene – a selective estrogen receptor modulator. The research was conducted by applying high-performance liquid chromatography on a 5 μm Zorbax Eclipse XDB-C18 column. Selective fluorescence detection (FL) was performed at an excitation of 219 nm and emission of 360 nm for TRP and KYNA. The assays showed good linearity (R2 >0.95) within the tested ranges of 0.045-0.20 µg mL−1, 0.025-0.32 µg mL−1, respectively, for KYNA and TRP. The limits of the detection were found to be 0.1480 ng mL−1 for KYNA and 0.0332 ng mL-1 for TRP. The deproteinization of the liver homogenate samples was accomplished by 80% methanol addition combined with boiling precipitation. The average recovery values were between 94.84% and 99.54% with RSDs no more than 5.5%. The work revealed that raloxifene decreased the mean value of tryptophan, as compared with the control group, while simultaneously leaving kynurenic acid at the same level. For the first time the research suggests that, in the case of raloxifene therapy, tryptophan is not metabolized via the kynurenine pathway.