A novel and easy protocol to obtain 6-alkoxy-Δ4,6-diene-3-one derivatives from available sterols.

Herein we report an unprecedented and efficient methodology for accessing 6-alkoxy-Δ4,6-diene-3-one derivatives. Such scaffolds were serendipitously obtained in the course of the study of the reaction of Δ4-3-keto steroids with catalytic amounts of iodine in refluxing methanol. A series of 6-methoxy and 6-ethoxy- Δ4,6-diene-3-ones were prepared from easily-available sterols in a two-step sequence; first, oxidation of sterols furnished the Δ4-3-keto steroids, which were then refluxed with ethanol or methanol with I2 as catalyst to obtain a series of ten derivatives. Furthermore, this protocol was also effective for the introduction of a larger carbon chain at C-6. Druglikeliness properties of synthesized compounds were predicted using the SwissADME tool.

Fibrillar Collagen Type I Participates in the Survival and Aggregation of Primary Hepatocytes Cultured on Soft Hydrogels.

Liver is an essential organ that carries out multiple functions such as glycogen storage, the synthesis of plasma proteins, and the detoxification of xenobiotics. Hepatocytes are the parenchyma that sustain almost all the functions supported by this organ. Hepatocytes and non-parenchymal cells respond to the mechanical alterations that occur in the extracellular matrix (ECM) caused by organogenesis and regenerating processes. Rearrangements of the ECM modify the composition and mechanical properties that result in specific dedifferentiation programs inside the hepatic cells. Quiescent hepatocytes are embedded in the soft ECM, which contains an important concentration of fibrillar collagens in combination with a basement membrane-associated matrix (BM). This work aims to evaluate the role of fibrillar collagens and BM on actin cytoskeleton organization and the function of rat primary hepatocytes cultured on soft elastic polyacrylamide hydrogels (PAA HGs). We used rat tail collagen type I and Matrigel® as references of fibrillar collagens and BM respectively and mixed different percentages of collagen type I in combination with BM. We also used peptides obtained from decellularized liver matrices (dECM). Remarkably, hepatocytes showed a poor adhesion in the absence of collagen on soft PAA HGs. We demonstrated that collagen type I inhibited apoptosis and activated extracellular signal-regulated kinases 1/2 (ERK1/2) in primary hepatocytes cultured on soft hydrogels. Epidermal growth factor (EGF) was not able to rescue cell viability in conjugated BM but affected cell aggregation in soft PAA HGs conjugated with combinations of different proportions of collagen and BM. Interestingly, actin cytoskeleton was localized and preserved close to plasma membrane (cortical actin) and proximal to intercellular ducts (canaliculi-like structures) in soft conditions; however, albumin protein expression was not preserved, even though primary hepatocytes did not remodel their actin cytoskeleton significantly in soft conditions. This investigation highlights the important role of fibrillar collagens on soft hydrogels for the maintenance of survival and aggregation of the hepatocytes. Data suggest evaluating the conditions that allow the establishment of optimal biomimetic environments for physiology and cell biology studies, where the phenotype of primary cells may be preserved for longer periods of time.

Fructose-1,6-bisphosphate reduces the mortality in Candida albicans bloodstream infection and prevents the septic-induced platelet decrease.

Due to the fact that an increased number of patients have experienced bloodstream infections caused by Candida species and the high mortality of this infection, there is a need for a strategy to reduce this scenery. One possible strategy is the use of new drugs, such as fructose-1,6-bisphosphate (FBP), which is a high-energy glycolytic metabolite and has shown to have therapeutic effects in several pathological conditions such as ischemia, shock, toxic injuries, and bacterial sepsis. The aim of this manuscript was to determine the role of FBP in experimental Candida albicans bloodstream infection. We used mice that were divided into three experimental groups: sham (not induced), bloodstream infection (induced with intratracheal instillation of C. albicans) and FBP (bloodstream infection plus FBP 500 mg/kg i.p.). Blood was taken for assessment of complete hematological profile and cytokine assay (IL-6 and MCP-1). Results of the study demonstrated that mortality decreased significantly in groups that received FBP. All cytokine and hematological indexes of FBP group were similar to bloodstream infection group with exception of platelets count. FBP significantly prevented the decrease in platelets. Taken together, our results demonstrate that FBP prevented the mortality in C. albicans bloodstream infection.

Fructose-1,6-bisphosphate protects against Zymosan-induced acute lung injury in mice.

It has been previously showed that fructose-1,6-bisphosphate (FBP) has anti-inflammatory and immunomodulatory effects on several experimental inflammation models. However, the effects and mechanism of FBP on Zymosan-induced acute lung injury (ALI) in mice had not been tested. In this study, our aim was to assess the anti-inflammatory activities of FBP on Zymosan-induced ALI. We found that in vivo treatment with FBP (500 mg/kg i.p.) markedly decreased the nitric oxide (NO) levels in the lungs and significantly reduced bronchoalveolar lavage fluid total cell and neutrophil counts and protein exudation after Zymosan challenge. Furthermore, FBP inhibited inducible nitric oxide synthase (iNOS) activities in RAW macrophages. Meanwhile, FBP did not inhibit the cyclooxigenase 2, interleukin-6, and nuclear factor kappa B transcription. Taken together, these results suggest that FBP shows anti-inflammatory effects through inhibiting lung edema, NO, and iNOS activities.