Primary dysmenorrhea is one of the most common reasons for gynecologic visits, but due to the lack of suitable animal models, the pathologic mechanisms and related drug development are limited. Herein, we establish a new mouse model which can mimic the periodic occurrence of primary dysmenorrhea to solve this problem. Non-pregnant female mice were pretreated with estradiol benzoate for 3 consecutive days. After that, mice were injected with oxytocin to simulate menstrual pain on the 4th, 8th, 12th, and 16th days (four estrus cycles). Assessment of the cumulative writhing score, uterine tissue morphology, and uterine artery blood flow and biochemical analysis were performed at each time point. Oxytocin injection induced an equally severe writhing reaction and increased PGF_2α accompanied with upregulated expression of COX-2 on the 4th and 8th days. In addition, decreased uterine artery blood flow but increased resistive index (RI) and pulsatility index (PI) were also observed. Furthermore, the metabolomics analysis results indicated that arachidonic acid metabolism; linoleic acid metabolism; glycerophospholipid metabolism; valine, leucine, and isoleucine biosynthesis; alpha-linolenic acid metabolism; and biosynthesis of unsaturated fatty acids might play important roles in the recurrence of primary dysmenorrhea. This new mouse model is able to mimic the clinical characteristics of primary dysmenorrhea for up to two estrous cycles.

Stroke is one of the most common neurological disorders and seriously threatens human life. Gross saponins of Tribulus terrestris fruit (GSTTF) are used for neuroprotective treatment on convalescents of ischemic stroke. However, the therapeutic effects and mechanisms have not yet well understood, especially from the metabolic perspective. In this study, the protective effect of GSTTF on ischemic stroke in a middle cerebral artery occlusion (MCAO) rat model was investigated by the GC-MS-based metabolomics approach. 2,3,5-triphenyltetrazolium chloride (TTC) staining of brain tissues showed that GSTTF significantly reduced the infarct area after MCAO surgery. Metabolomic profiling showed a series of metabolic perturbation occurs in ischemic stroke compared with sham group. GSTTF can reverse the MCAO-induced serum metabolic deviations by regulating multiple metabolic pathways including fatty acids metabolism, amino acids metabolism, and carbohydrates metabolism. The current study provided a useful approach for understanding the mechanism of MCAO-induced ischemic stroke and a reliable basis for evaluating the efficacy of GSTTF in the treatment of ischemic stroke.

The phosphatases INPP4B and PTEN are tumor suppressors that are lost in nearly half of advanced metastatic cancers. The loss of PTEN in prostate epithelium initially leads to an upregulation of several tumor suppressors that slow the progression of prostate cancer in mouse models. We tested whether the loss of INPP4B elicits a similar compensatory response in prostate tissue and whether this response is distinct from the one caused by the loss of PTEN. Knockdown of INPP4B but not PTEN in human prostate cancer cell lines caused a decrease in EZH2 expression. In Inpp4b^−/− mouse prostate epithelium, EZH2 levels were decreased, as were methylation levels of histone H3. In contrast, Ezh2 levels were increased in the prostates of Pten^−/− male mice. Contrary to PTEN, there was a positive correlation between INPP4B and EZH2 expression in normal human prostates and early-stage prostate tumors. Analysis of single-cell transcriptomic data demonstrated that a subset of EZH2-positive cells expresses INPP4B or PTEN, but rarely both, consistent with their opposing correlation with EZH2 expression. Unlike PTEN, INPP4B did not affect the levels of SMAD4 protein expression or Pml mRNA expression. Like PTEN, p53 protein expression and phosphorylation of Akt in Inpp4b^−/− murine prostates were elevated. Taken together, the loss of INPP4B in the prostate leads to overlapping and distinct changes in tumor suppressor and oncogenic downstream signaling.

Authors: Yasemin Ceyhan, Manqi Zhang, Yanhao Lai, Judy L. Vasquez, Yuan Liu, Irina U. Agoulnik, Yuk-Ching Tse-Dinh Affiliations: Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA, Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA, Department of Environmental