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Aromatase inhibitors, which inhibit the conversion of androgens to estrogens, have had extensive use for more than 40 years to treat postmenopausal breast cancer as well as used in clinical studies for endometrial, ovarian cancers, and endometriosis. [...]showing the importance of targeting estrogen formation and metabolism in cancer treatment, sulfatase inhibitors that target the enzyme responsible for the hydrolysis of inactive estrogen-sulfates have entered clinical trials for the treatment of breast, endometrial cancers, and endometriosis, primarily demonstrating effects in breast cancer. Deficiency in BH4 leads to various symptoms in the peripheral and central nervous systems. [...]an ideal therapeutic approach would involve blocking excessive BH4 production while preventing BH4 depletion. [...]the current Research Topic included an original article that presented the role of cyclic nucleotides, specifically 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP), in fundamental brain functions, including learning and memory.Yanai et al.demonstrated that phosphodiesterase 3 (PDE3) regulated the cellular content of cAMP and cGMP, which is in agreement with previous studies showing that long-term administration of cilostazol, a PDE3 inhibitor, improved memory performance in aging mice.

Women who decide to pursue a scientific career, focusing on gastroenterology, face many challenges, including funding of research, the time constraints to juggle a clinical and research career and the process of research itself including obtaining data protection clearance, data collection and statistical analysis of data and the publication process that can be lengthy. There has been extensive research in the development of non-invasive markers in patients with inflammatory bowel disease that reflect disease activity. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure. After exogenous administration of VEGFA in steatotic animals, circulating VEGFA is sequestered by the high circulating levels of sFlt1 released from adipose tissue. Under such conditions, VEGFA cannot reach the steatotic liver to exert its effects. Consequently, the concomitant administration of VEGFA and an antibody against sFlt1 was required to avoid binding of sFlt1 to VEGFA. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure, plus improvement in the survival rate via up-regulation of PI3K/Akt independently of the Id1-Wnt2 pathway. The current study highlights the different effects and signaling pathways of VEGFA in liver surgery requiring PH and I/R based in the presence of steatosis.Key messagesVEGFA administration improves PH+I/R injury only in non-steatotic livers of Ln animals.VEGFA benefits are exerted through the VEGFR2-Wnt2 pathway in non-steatotic livers.In Ob rats, exogenous VEGFA is sequestered by circulating sFlt1, exacerbating liver damage.Therapeutic combination of VEGFA and anti-sFlt1 is required to protect steatotic livers.VEGFA+anti-sFlt1 treatment protects steatotic livers through a VEGFR2-PI3K/Akt pathway.

Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.