Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A 2B adenosine receptor-mediated (A 2B R-mediated) cAMP and cGMP induction was required for elevated adenosine-induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A 2B R activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A 2B R signaling in both Ada -/-and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A 2B R activation may prove beneficial in the treatment of this disorder.

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA–oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.

Crystalloid-based resuscitation of severely injured trauma patients leads to intestinal edema. A potential mechanism of intestinal edema-induced ileus is a reduction of myosin light chain phosphorylation in intestinal smooth muscle. We sought to determine if the onset of edema initiated a measurable, early mechanotransductive signal and if hypertonic saline (HS) can modulate this early signal by changing intestinal fluid balance. An anesthetized rat model of acute interstitial intestinal edema was used. At laparotomy, the mesenteric lymphatic was cannulated to measure lymph flow and pressure, and a fluid-filled micropipette was placed in the intestinal submucosa to measure interstitial pressure. Rats were randomized into four groups (n=6 per group): sham, mesenteric venous hypertension+80 mL/kg 0.9% isotonic sodium chloride solution (ISCS 80), mesenteric venous hypertension+80 mL/kg 0.9% ISCS+4 mL/kg 7.5% saline (ISCS 80+HS), or 4 mL/kg 7.5% saline (HS alone) to receive the aforementioned intravenous fluid administered over 5 min. Measurements were made 30 min after completion of the preparation. Tissue water, lymph flow, and interstitial pressure were measured. Resultant applied volume induced stress on the smooth muscle (sigmaravi-muscularis) was calculated. Mesenteric venous hypertension and crystalloid resuscitation caused intestinal edema that was prevented by HS. Intestinal edema caused an early increase in intestinal interstitial pressure that was prevented by HS. Hypertonic saline did not augment lymphatic removal of intestinal edema. sigmaravi-muscularis was increased with onset of edema and prevented by HS, paralleling the interstitial pressure data. Intestinal edema causes an early increase in interstitial pressure that is prevented by HS. Prevention of the edema-induced increase in interstitial pressure serves to blunt the mechanotransductive signal of sigmaravi-muscularis.

We previously demonstrated that the intravenous delivery of multipotent adult progenitor cells (MAPCs) after traumatic brain injury (TBI) in rodents provides neuroprotection by preserving the blood-brain barrier and systemically attenuating inflammation in the acute time frame following cell treatment; however, the long-term behavioral and anti-inflammatory effects of MAPC administration after TBI have yet to be explored. We hypothesized that the intravenous injection of MAPCs after TBI attenuates the inflammatory response (as measured by microglial morphology) and improves performance at motor tasks and spatial learning (Morris water maze [MWM]). MAPCs were administered intravenously 2 and 24 hours after a cortical contusion injury (CCI). We tested four groups at 120 days after TBI: sham (uninjured), injured but not treated (CCI), and injured and treated with one of two concentrations of MAPCs, either 2 million cells per kilogram (CCI-2) or 10 million cells per kilogram (CCI-10). CCI-10 rats showed significant improvement in left hind limb deficit on the balance beam. On the fifth day of MWM trials, CCI-10 animals showed a significant decrease in both latency to platform and distance traveled compared with CCI. Probe trials revealed a significant decrease in proximity measure in CCI-10 compared with CCI, suggesting improved memory retrieval. Neuroinflammation was quantified by enumerating activated microglia in the ipsilateral hippocampus. We observed a significant decrease in the number of activated microglia in the dentate gyrus in CCI-10 compared with CCI. Our results demonstrate that intravenous MAPC treatment after TBI in a rodent model offers long-term improvements in spatial learning as well as attenuation of neuroinflammation. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:953-960

Ovarian cancer is characterized by dysbiosis, referred to as oncobiosis in neoplastic diseases. In ovarian cancer, oncobiosis was identified in numerous compartments, including the tumor tissue itself, the upper and lower female genital tract, serum, peritoneum, and the intestines. Colonization was linked to Gram-negative bacteria with high inflammatory potential. Local inflammation probably participates in the initiation and continuation of carcinogenesis. Furthermore, local bacterial colonies in the peritoneum may facilitate metastasis formation in ovarian cancer. Vaginal infections (e.g. Neisseria gonorrhoeae or Chlamydia trachomatis) increase the risk of developing ovarian cancer. Bacterial metabolites, produced by the healthy eubiome or the oncobiome, may exert autocrine, paracrine, and hormone-like effects, as was evidenced in breast cancer or pancreas adenocarcinoma. We discuss the possible involvement of lipopolysaccharides, lysophosphatides and tryptophan metabolites, as well as, short-chain fatty acids, secondary bile acids and polyamines in the carcinogenesis of ovarian cancer. We discuss the applicability of nutrients, antibiotics, and probiotics to harness the microbiome and support ovarian cancer therapy. The oncobiome and the most likely bacterial metabolites play vital roles in mediating the effectiveness of chemotherapy. Finally, we discuss the potential of oncobiotic changes as biomarkers for the diagnosis of ovarian cancer and microbial metabolites as possible adjuvant agents in therapy.

We conclude that edema decreases myosin light chain phosphorylation, leading to decreased intestinal contractile activity.

Background Patients with traumatic brain injury (TBI) often suffer from gastrointestinal dysfunction including intolerance to enteral feedings. However, it is unclear how TBI affects small intestinal contractile activity. The purpose of this study was to determine if TBI affects intestinal smooth muscle function. Methods Sprague–Dawley rats were subjected to controlled cortical impact injury (TBI). Sham animals underwent a similar surgery but no injury (SHAM). Animals were sacrificed 1, 3, and 7 days after TBI and intestinal smooth muscle tissue was collected for measurement of contractile activity and transit, NF-kB activity, and cytokine levels. Brains were collected after sacrifice to determine volume loss due to injury. Key Results Contractile activity decreased significantly in ileum, but not jejunum, in the TBI group 7 days after injury compared with SHAM. Brain volume loss increased significantly 7 days after injury compared with 3 days and correlated significantly with the contractile activity 1 day after injury. In the intestinal smooth muscle, NF-kB activity increased significantly in the TBI group 3 and 7 days after injury vs SHAM. Wet to dry weight ratio, indicating edema, also increased significantly in the TBI group. Interleukin- 1α, -1β, and -17 increased significantly in the TBI group compared with SHAM. Conclusions & Inferences Traumatic brain injury causes a delayed but significant decrease in intestinal contractile activity in the ileum leading to delayed transit. The decreased intestinal contractile activity is attributed to secondary inflammatory injury as evidenced by increased NF-kB activity, increased edema, and increased inflammatory cytokines in the intestinal smooth muscle.

High volume resuscitation and damage control surgical methods, while responsible for significantly decreasing morbidity and mortality from traumatic injuries, are associated with pathophysiological derangements that lead to subsequent end organ edema and dysfunction. Alterations in hydrostatic and oncotic pressures frequently result in intestinal edema and subsequent dysfunction. The purpose of this review is to examine the principles involved in the development of intestinal edema, current and historical models for the study of edema, effects of edema on intestinal function (particularly ileus), molecular mediators governing edema-induced dysfunction, potential role of mechanotransduction, and therapeutic effects of hypertonic saline. We review the current state of the science as it relates to resuscitation induced intestinal edema and resultant dysfunction.