LXA4 protected mice from renal ischemia/reperfusion injury by promoting IRG1/Nrf2 and IRAK-M-TRAF6 signal pathways.

Excessive inflammatory response and increased oxidative stress play an essential role in the pathophysiology of ischemia/reperfusion (I/R)-induced acute kidney injury (IRI-AKI). Emerging evidence suggests that lipoxin A4 (LXA4), as an endogenous negative regulator in inflammation, can ameliorate several I/R injuries. However, the mechanisms and effects of LXA4 on IRI-AKI remain unknown. In this study, A bilateral renal I/R mouse model was used to evaluate the role of LXA4 in wild-type, IRG1 knockout, and IRAK-M knockout mice. Our results showed that LXA4, as well as 5-LOX and ALXR, were quickly induced, and subsequently decreased by renal I/R. LXA4 pretreatment improved renal I/R-induced renal function impairment and renal damage and inhibited inflammatory responses and oxidative stresses in mice kidneys. Notably, LXA4 inhibited I/R-induced the activation of TLR4 signal pathway including decreased phosphorylation of TAK1, p36, and p65, but did not affect TLR4 and p-IRAK-1. The analysis of transcriptomic sequencing data and immunoblotting suggested that innate immune signal molecules interleukin-1 receptor-associated kinase-M (IRAK-M) and immunoresponsive gene 1 (IRG1) might be the key targets of LXA4. Further, the knockout of IRG1 or IRAK-M abolished the beneficial effects of LXA4 on IRI-AKI. In addition, IRG1 deficiency reversed the up-regulation of IRAK-M by LXA4, while IRAK-M knockout had no impact on the IRG1 expression, indicating that IRAK-M is a downstream molecule of IRG1. Mechanistically, we found that LXA4-promoted IRG1-itaconate not only enhanced Nrf2 activation and increased HO-1 and NQO1, but also upregulated IRAK-M, which interacted with TRAF6 by competing with IRAK-1, resulting in deactivation of TLR4 downstream signal in IRI-AKI. These data suggested that LXA4 protected against IRI-AKI via promoting IRG1/Itaconate-Nrf2 and IRAK-M-TRAF6 signaling pathways, providing the rationale for a novel strategy for preventing and treating IRI-AKI.

Pd(II)-Catalyzed Synthesis of Polycyclic Heteroarenes via an Aminopalladation/C-H Activation/Dealkylation/Decarboxylative Cyclization Cascade.

Until now, cascade reactions involving five-membered C,C-palladacycles rely heavily on Pd(0)-catalyzed C-H functionalization of aryl halides initiated by carbopalladation. Herein, we report a novel Pd(II)-catalyzed cascade decarboxylative cyclization of o-alkynylanilines initiated by aminopalladation. In this protocol, o-alkynylanilines undergo sequential anti aminopalladation, C-H activation, and dealkylation to form C,C-palladacycles, which are then trapped by o-bromobenzoic acids or 8-bromo-1-naphthoic acid to produce diverse polycyclic heteroarenes, such as dibenzo[a,c]carbazoles and multiple arene-fused cyclohepta[1,2-b]indoles.

Palladium-Catalyzed [4 + 3] or [2 + 2 + 3] Annulation via C-H Activation and Subsequent Decarboxylation: Access to Heptagon-Embedded Polycyclic Aromatic Hydrocarbons.

The construction of a seven-membered ring in the polycyclic aromatic hydrocarbon skeleton remains a notoriously difficult but attractive challenge. Herein a novel palladium-catalyzed [4 + 3] decarboxylative annulation of 2-iodobiphenyls with 2-(2-halophenyl)acrylic acids is reported, which provides an efficient approach for assembling various tribenzo[7]annulenes via a C-H activation and decarboxylation process. Moreover, tribenzo[7]annulenes can be also synthesized via a [2 + 2 + 3] decarboxylative annulation strategy by employing readily available 1,2-halobenzenes, phenylboronic acids, and 2-(2-halophenyl)acrylic acids.

CuI/2-Aminopyridine 1-Oxide Catalyzed Amination of Aryl Chlorides with Aliphatic Amines.

A class of 2-aminopyridine 1-oxides are discovered to be effective ligands for the Cu-catalyzed amination of less reactive (hetero)aryl chlorides. A wide range of functionalized (hetero)aryl chlorides reacted with various aliphatic amines to afford the desired products in good to excellent yields under the catalyst of CuI/2-aminopyridine 1-oxides. Furthermore, the catalyst system worked well for the coupling of cyclic secondary amines and N-methyl benzylamine with (hetero)aryl chlorides.

Ferulic Acid Protected from Kidney Ischemia Reperfusion Injury in Mice: Possible Mechanism Through Increasing Adenosine Generation via HIF-1α.

Ferulic acid (FA), derived from fruits and vegetables, is well-known as a potent antioxidant of scavenging free radicals. However, the role and underlying mechanism of FA on kidney ischemia reperfusion (I/R) injury are limited. Here, we explored the effects of FA on kidney I/R injury. The kidney I/R injury models were carried out by clamping bilateral pedicles for 35 min followed by reperfusion for 24 h. Mice were orally pretreated with different doses of FA for three times 24 h before I/R. The renal function was assessed by serum creatine (Scr) and blood urea nitrogen (BUN). Kidney histology was examined by hematoxylin and eosin (HE) staining and terminal deoxynucleotidly transferased UTP nick-end labeling (TUNEL) assay. Proinflammatory cytokines, caspase-3 activity, adenosine generation, adenosine signaling molecules, and hypoxia inducible factor-1 alpha (HIF-1α) were also detected, respectively. The siHIF-1α adenovirus vectors were in vivo used to inhibit the expression of HIF-1α. The results showed that FA significantly attenuated kidney damage in renal I/R-operated mice as indicated by reducing levels of Scr and BUN, ameliorating renal pathological structural changes, and tubular cells apoptosis. Moreover, FA pretreatment inhibited I/R-induced renal proinflammatory cytokines and neutrophils recruitment. Interestingly, the levels of HIF-α, CD39, and CD73 mRNA and protein as well as adenosine production were all significantly increased after FA pretreatment in the kidney of I/R-performed mice, and inhibiting HIF-α expression using siRNA abolished this protection of FA on I/R-induced acute kidney injury as evidenced by more severe renal damage and reduced adenosine production. Our findings indicated that FA protected against kidney I/R injury by reducing apoptosis, alleviating inflammation, increasing adenosine generation, and upregulating CD39 and CD73 expression, which might be mediated by HIF-1α.

Paeoniflorin protects against liver ischemia/reperfusion injury in mice via inhibiting HMGB1-TLR4 signaling pathway.

Hepatic ischemia/reperfusion (I/R) injury is a major cause of high morbidity and mortality after liver resection, transplantation, and hemorrhagic shock. Paeoniflorin (PF), the main substance of glucosides in Radix Paeoniae Alba, has been widely used to treat various hepatic inflammatory diseases including I/R injury. However, the underlying mechanisms of PF on hepatic I/R injury remain further investigated. In this study, the liver I/R model was performed by clamping the portal vein and hepatic artery with an atraumatic clamp for 90 min followed by 6 hr reperfusion. PF (100 mg/kg) was given three times a day by gavage before I/R. The blood and hepatic samples were collected to evaluate liver injury and molecular indexes. The results showed that PF pretreatment significantly inhibited I/R-induced serum ALT and AST activities (40.3% and 53.8% those of I/R group, respectively), hepatic pathological damages and hepatic apoptosis (P < 0.01), and infiltration of neutrophils into liver. In addition, PF suppressed the production of pro-inflammatory cytokines (P < 0.01), decreased the expression of high mobility group box-1 (HMGB1), and down-regulated toll-like receptors 4 (TLR4) and phosphorylated ERK1/2, JNK1/2, p38, and NF-κB signal molecules expression in the I/R-operated mice. These findings indicated that PF played a protective role in liver I/R injury, and this protection was associated with inhibition of I/R-activated HMGB1-TLR4 signaling pathway to attenuate hepatic inflammation responses.

Resolvin D1 attenuates CCl4-induced acute liver injury involving up-regulation of HO-1 in mice.

Acute hepatic failure involves in excessive oxidative stress and inflammatory responses, leading to a high mortality due to lacking effective therapy. Resolvin D1 (RvD1), an endogenous lipid mediator derived from polyunsaturated fatty acids, has been shown anti-inflammatory and anti-oxidative actions, however, whether RvD1 has protective effects on hepatic failure remains elusive. In this study, the roles and molecular mechanisms of RvD1 were explored in carbon tetrachloride (CCl4)-induced acute liver injury. Our results showed that RvD1 protected mice against CCl4-induced hepatic damage, as evaluated by reduced aminotransferase activities and malondialdehyde content, elevated glutathione and superoxide dismutase activities, and alleviated hepatic pathological damage. Moreover, RvD1 significantly attenuated serum tumor necrosis factor-α and interleukin-6 levels as well as hepatic myeloperoxidase activity, whereas enhanced serum IL-10 level in CCl4-administered mice. Further, RvD1 markedly up-regulated the expression and activity of heme oxygenase-1 (HO-1). However, inhibition of HO-1 activity reversed the protective effects of RvD1 on CCl4-induced liver injury. These results suggest that RvD1 could effectively prevent CCl4-induced liver injury by inhibition of oxidative stress and inflammation, and the underlying mechanism may be related to up-regulation of HO-1.