Synthesis of remote fluoroalkenyl ketones by photo-induced ring-opening addition of cyclic alkoxy radicals to fluorinated alkenes.

Fluoroalkenyl moieties are often used as carbonyl mimics in medicine preparation, and thus the development of facile routes for the synthesis of such compounds is of great importance. In this work, we report a photocatalytic ring-opening addition of cyclic alcohols to α-(trifluoromethyl)styrenes, which underwent a proton-coupled electron transfer and ß-scission process, delivering a great variety of remote gem-difluoroalkenyl ketone derivatives. This methodology can also be applied in the reaction of gem-difluorostyrenes and 1,1,2-trifluorostyrenes to access monofluoro- and 1,2-difluoroalkenyl ketones.

Camel whey protein alleviates heat stress-induced liver injury by activating the Nrf2/HO-1 signaling pathway and inhibiting HMGB1 release.

This study aimed to investigate the mechanism by which camel whey protein (CWP) inhibits the release of high-mobility group box 1 (HMGB1) in heat stress (HS)-stimulated rat liver. Administration of CWP by gavage prior to HS inhibited the cytoplasmic translocation of HMGB1 and consequently reduced the inflammatory response in the rat liver, and downregulated the levels of the NLR pyrin domain containing 3 (NLRP3) inflammasome, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α. The use of N-acetyl-L-cysteine (NAC), an inhibitor of reactive oxygen species (ROS) production, indicated that this downregulation effect may be attributed to the antioxidant activity of CWP. We observed that CWP enhanced nuclear factor erythroid 2-related factor (Nrf)2 and heme-oxygenase (HO)-1 expression, which inhibited ROS production, nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity, and malondialdehyde (MDA) levels, and increased superoxide dismutase 1 (SOD1) activity and reduced glutathione (GSH) content in the HS-treated liver, ultimately increasing the total antioxidant capacity (TAC) in the liver. Administration of Nrf2 or HO-1 inhibitors before HS abolished the protective effects of CWP against oxidative damage in the liver of HS-treated rats, accompanied by increased levels of HMGB1 in the cytoplasm and IL-1ß and TNF-α in the serum. In conclusion, our study demonstrated that CWP enhanced the TAC of the rat liver after HS by activating Nrf2/HO-1 signaling, which in turn reduced HMGB1 release from hepatocytes and the subsequent inflammatory response and damage. Furthermore, the combination of CWP and NAC abolished the adverse effects of HS in the rat liver. Therefore, dietary CWP could be an effective adjuvant treatment for HS-induced liver damage.

ß-Glucan from Saccharomyces cerevisiae alleviates oxidative stress in LPS-stimulated RAW264.7 cells via Dectin-1/Nrf2/HO-1 signaling pathway.

ß-Glucan from Saccharomyces cerevisiae has been described to be effective antioxidants, but the specific antioxidation mechanism of ß-glucan is unclear. The objectives of this research were to determine whether the ß-glucan from Saccharomyces cerevisiae could regulate oxidative stress through the Dectin-1/Nrf2/HO-1 signaling pathway in lipopolysaccharides (LPS)-stimulated RAW264.7 cells. In this study, we examined the effects of ß-glucan on the enzyme activity or production of oxidative stress indicators in LPS-stimulated RAW264.7 cells by biochemical analysis and the protein expression of key factors of Dectin-1/Nrf2/HO-1 signaling pathway by immunofluorescence and western blot. The biochemical analysis results showed that ß-glucan increased the LPS-induced downregulation of enzyme activity of intracellular heme oxygenase (HO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) while decreasing the production of reactive oxygen species (ROS) and malondialdehyde (MDA). Furthermore, immunofluorescence results showed that ß-glucan can activate the nuclear factor erythroid 2-related factor 2 (Nrf2). The antioxidant mechanism study indicated that ß-glucan activated dendritic-cell-associated C-type lectin 1 (Dectin-1) receptors mediated Nrf2/HO-1 signaling pathway, thereby downregulating the production of ROS and thus produced the antioxidant effects in LPS-stimulated RAW 264.7 cells. In conclusion, these results indicate that ß-glucan potently alleviated oxidative stress via Dectin-1/Nrf2/HO-1 in LPS-stimulated RAW 264.7 cells.

Hydrolyzed camel whey protein alleviated heat stress-induced hepatocyte damage by activated Nrf2/HO-1 signaling pathway and inhibited NF-κB/NLRP3 axis.

Liver damage is the most severe complication of heat stress (HS). Hydrolyzed camel whey protein (CWP) possesses bioactive peptides with obviously antioxidant and anti-inflammatory activities. The current study aims to investigate whether CWP that is hydrolyzed by a simulated gastrointestinal digestion process, named S-CWP, protects BRL-3A hepatocytes from HS-induced damage via antioxidant and anti-inflammatory mechanisms. BRL-3A cells were pretreated with S-CWP before being treated at 43 °C for 1 h, and the levels of the cellular oxidative stress, inflammation, apoptosis, biomarkers for liver function, the activities of several antioxidant enzymes, and the cell viability were analyzed. The expression level of pivotal proteins in correlative signaling pathways was evaluated by western blotting. We confirmed that S-CWP alleviated HS-induced hepatocytes oxidative stress by decreased reactive oxygen species (ROS), nitric oxide (NO), 8-Hydroxy-2'-deoxyguanosine (8-OHdG), lipid peroxidation (LPO), protein carbonylation (PCO), and the activities of NADPH oxidase while enhanced superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1) activities, and GSH content. S-CWP suppressed HS-induced inflammatory response by reducing the phosphorylation of NF-κB p65, the expression of NLRP3, and caspase-1 and finally alleviated caspase-3-mediated apoptosis. S-CWP also alleviated HS-induced hepatocyte injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and restoring Heat Shock Protein 70 (HSP70) expression. Furthermore, S-CWP treatment significantly enhanced the expression of NF-E2-related nuclear factor erythroid-2 (Nrf2) and HO-1. The antioxidant and anti-inflammatory effects of S-CWP were weakened by ML385, a specific Nrf2 inhibitor. Additionally, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, significantly reversed S-CWP-induced reduction in the phosphorylation of NF-κB p65. Thus, our results revealed that S-CWP protected against HS-induced hepatocytes damage via activating the Nrf2/HO-1 signaling pathway and inhibiting NF-κB/NLRP3 axis.

Regulation of Hedgehog signaling Offers A Novel Perspective for Bone Homeostasis Disorder Treatment.

The hedgehog (HH) signaling pathway is central to the regulation of bone development and homeostasis. HH signaling is not only involved in osteoblast differentiation from bone marrow mesenchymal stem cells (BM-MSCs), but also acts upstream within osteoblasts via the OPG/RANK/RANKL axis to control the expression of RANKL. HH signaling has been found to up-regulate parathyroid hormone related protein (PTHrP) expression in osteoblasts, which in turn activates its downstream targets nuclear factor of activated T cells (NFAT) and cAMP responsive element binding protein (CREB), and as a result CREB and NFAT cooperatively increase RANKL expression and osteoclastogenesis. Osteoblasts must remain in balance with osteoclasts in order to avoid excessive bone formation or resorption, thereby maintaining bone homeostasis. This review systemically summarizes the mechanisms whereby HH signaling induces osteoblast development and controls RANKL expression through PTHrP in osteoblasts. Proper targeting of HH signaling may offer a therapeutic option for treating bone homeostasis disorders.

Cp*CoIII-Catalyzed Synthesis of Pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-iums via Tandem C-H Activation and Subsequent Annulation from 1-(Pyridin-2-yl)-1H-indoles and Internal Alkynes.

A Cp*CoIII-catalyzed C2-selective C-H alkenylation/annulation cascade transformation of 1-(pyridin-2-yl)-1H-indoles with internal alkynes to afford pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-iums is presented. Moreover, 6,7-dihydro-4H-pyrido[2',1':2,3]pyrimido[1,6-a]indole, a new functionalized N-fused indole core heterocycle, could be constructed effectively via reduction of pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-ium by NaBH4.