No abstract

BackgroundThe phytoestrogen, genistein at low doses nongenomically activates mitogen-activated protein kinase p44/42 (MAPKp44/42) via estrogen receptor alpha (ERα) leading to proliferation of human uterine leiomyoma cells. In this study, we evaluated if MAPKp44/42 could activate downstream effectors such as mitogen- and stress-activated protein kinase 1 (MSK1), which could then epigenetically modify histone H3 by phosphorylation following a low dose (1 μg/ml) of genistein.ResultsUsing hormone-responsive immortalized human uterine leiomyoma (ht-UtLM) cells, we found that genistein activated MAPKp44/42 and MSK1, and also increased phosphorylation of histone H3 at serine10 (H3S10ph) in ht-UtLM cells. Colocalization of phosphorylated MSK1 and H3S10ph was evident by confocal microscopy in ht-UtLM cells (r = 0.8533). Phosphorylation of both MSK1and H3S10ph was abrogated by PD98059 (PD), a MEK1 kinase inhibitor, thereby supporting genistein’s activation of MSK1 and Histone H3 was downstream of MAPKp44/42. In proliferative (estrogenic) phase human uterine fibroid tissues, phosphorylated MSK1 and H3S10ph showed increased immunoexpression compared to normal myometrial tissues, similar to results observed in in vitro studies following low-dose genistein administration. Real-time RT-PCR arrays showed induction of growth-related transcription factor genes, EGR1, Elk1, ID1, and MYB (cMyb) with confirmation by western blot, downstream of MAPK in response to low-dose genistein in ht-UtLM cells. Additionally, genistein induced associations of promoter regions of the above transcription factors with H3S10ph as evidenced by Chromatin Immunoprecipitation (ChIP) assays, which were inhibited by PD. Therefore, genistein epigenetically modified histone H3 by phosphorylation of serine 10, which was regulated by MSK1 and MAPK activation.ConclusionHistone H3 phosphorylation possibly represents a mechanism whereby increased transcriptional activation occurs following low-dose genistein exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-016-0141-2) contains supplementary material, which is available to authorized users.

As the gut microbiota continues to be implicated in an increasing number of disease processes, a plethora of new literature surrounding its complexity and role in the maintenance of intestinal homeostasis has become available. Non-alcoholic fatty liver disease (NAFLD) has become the most common nonviral liver disease worldwide and a number of predisposing risk factors for NAFLD have been identified, including obesity and insulin resistance. Recent evidence supports a role for the gut microbiota in the pathogenesis of these risk factors and NAFLD, itself. Additionally, changes in the gut microbiota can lead to activation of immune responses that have the potential to promote progression of NAFLD to the more severe Nonalcoholic steatohepatitis (NASH). Furthermore, the gut microbiota may serve as a potential target for therapeutic options to treat NAFLD. This review seeks to explain the role of the gut microbiota in the pathogenesis of NAFLD and its risk factors, while also discussing potential future treatment options directed at correcting imbalances with in the gut microbiota.

INTRODUCTION: Salivary gland tumors are rare, often benign, mostly originating from the parotid gland. Tumors can also arise from submandibular and sublingual glands, and while these tumors tend to be more rare, they are more often malignant. Salivary gland tumors usually metastasize to the lung, bone, and liver. CASE DESCRIPTION/METHODS: A 77-year-old Albanian male with history of a right-sided mandibular abscess s/p drainage in 2015 presented with confusion and abdominal pain. Labs were unremarkable. He underwent CT head, which was concerning for an occipital lesion, for which he proceeded with an MRI brain that revealed multiple intracranial lesions concerning for metastatic disease. He then had a CT Abdomen/Pelvis that revealed several hepatic lesions, innumerable pulmonary nodules, and an area of focal thickening and enhancement of the proximal ascending colon. Bone scan revealed likely metastasis to the L5 vertebral body. His CEA was 4.7 and CA 19-9 was 43.6. AFP was 1.7. He then had a colonoscopy, which was significant for 2 polyps in the descending colon, 2 umbilicated polyps in the transverse colon, a 4 mm sessile polyp in the transverse colon, and a submucosal and ulcerated non-obstructing mass in the proximal ascending colon distal to the ileocecal valve. Pathology showed small, round, blue cells with trabecular growth pattern and necrosis, consistent with invasive, poorly differentiated carcinoma with basaloid features. In addition, the immunohistochemistry was positive for CK7 and Sox10, focally positive for S100, and weakly positive for CD 117, all suggestive of an adenoid cystic carcinoma. Treatment first consisted of palliative radiation to his CNS lesions, a dexamethasone taper, and an Oncology consult for consideration of palliative chemotherapy. He was offered palliative paclitaxel and carboplatin, however he ultimately decided to return to Albania and forego treatment. DISCUSSION: This patient likely had undiagnosed, malignant, primary salivary gland cancer for many years; despite having his mandibular ‘abscess’ drained several years prior. In addition, the lesion metastasized to several uncommon locations, notably the brain and colon, which are the 2 sites that ultimately produced symptoms that prompted him to receive further medical care. Salivary gland tumors must be considered in patients presenting with head and neck swelling, and proper diagnostic workup must be obtained. In addition, uncommon sites of metastasis, such as colon, must be considered during staging of disease.

As the gut microbiota continues to be implicated in an increasing number of disease processes, a plethora of new literature surrounding its complexity and role in the maintenance of intestinal homeostasis has become available. Nonalcoholic fatty liver disease (NAFLD) has become the most common nonviral liver disease worldwide and a number of predisposing risk factors for NAFLD have been identified, including obesity and insulin resistance. Recent evidence supports a role for the gut microbiota in the pathogenesis of these risk factors and NAFLD itself. Additionally changes in the gut microbiota can lead to activation of immune responses that have the potential to promote progression of NAFLD to the more severe nonalcoholic steatohepatitis (NASH). Furthermore, the gut microbiota may serve as a potential target for therapeutic options to treat NAFLD. This review seeks to explain the role of the gut microbiota in the pathogenesis of NAFLD and its risk factors, while also discussing potential future treatment options directed at correcting imbalances with in the gut microbiota.