Photoredox-Catalyzed Tandem Radical Cyclization/Hydroxylation for the Synthesis of 4-Hydroxyalkyl-3,3-difluoro-γ-lactams.

The photoredox-catalyzed radical difluoroalkylation/cyclization/hydroxylation cascade reaction of various 2-bromo-2,2-difluoro-N-arylacetamides containing unactivated alkene moieties has been developed, providing green and efficient access to various 4-hydroxyalkyl-3,3-difluoro-γ-lactams. Control experiments confirmed a radical process, and inexpensive air acted as the sole hydroxy resource. In addition, the highlights of this protocol include good tolerance for a variety functional groups, lower photocatalyst loading, and ease of operation.

Photoinduced Cascade C-N/C═O Bond Formation from Bromodifluoroalkyl Reagents, Amines, and H2O via a Triple-Cleavage Process.

A green, sustainable, and straightforward method for the synthesis of unsymmetrical oxalamides via photoinduced C-N/C═O bond formation of bromodifluoroacetamide, amine, and H2O through a triple-cleavage process has been developed. In addition, this approach also provides access to the known bioactive compounds, and a feasible reaction mechanism is proposed. Moreover, the advantages of this transformation, including mild reaction conditions, a broad substrate scope, and operational simplicity, make this protocol attractive for further applications.

Photoinduced EDA Complexes Enabled Radical Tandem Cyclization/Arylation of Unactivated Alkene with 2-Amino-1,4-naphthoquinones.

A visible-light-induced radical tandem cyclization/arylation between 2-amino-1, 4-naphthoquinone and N-allyl-2-bromo-2,2-difluoroacetamides has been developed without an external photocatalyst. The transformation could be carried out at room temperature and gave a variety of C-3-functionalized 2-amino-1,4-naphthoquinone derivatives in moderate to excellent yields. Moreover, mechanistic studies revealed that the reaction is driven by the formation of an electron donor-acceptor (EDA) complex.

Fabrication of hydrophobic NiFe2O4@poly(DVB-LMA) sponge via a Pickering emulsion template method for oil/water separation.

Super-hydrophobic porous absorbents are convenient, low-cost, efficient and environment-friendly materials in the treatment of oil spills. In this work, a simple Pickering emulsion template method was employed to fabricate an interconnected porous poly(DVB-LMA) sponge. A new co-Pickering stabilization system of Span 80 and NiFe2O4 nanoparticles was used to prepare ultra-concentrated internal phase water-in-oil (W/O) emulsions. After further polymerization, the resulting sponges were generated, which exhibited excellent adsorption selectivity due to the super-hydrophobicity and super-lipophilicity. Furthermore, the characterization results indicated that the composites had superior thermal stability, low density, high porosity and a flexible three-dimensional porous structure. Besides, the addition of nickel ferrite nanoparticles provided the materials with extra magnetic operability. High oil adsorption capacity (up to 36.9-84.2 g g-1), high oil retention, fast adsorption rate and superior reusability allowed the materials to be applied in the treatment of oily water.

Visible Light/Tertiary Amine Promoted Synergistic Hydroxydifluoroacetamidation of Unactivated Alkenes under Air.

An efficient and novel method for regioselective hydroxydifluoroacetamidation of alkenes with bromodifluoroacetamides has been achieved via a tandem radical pathway mediated by photoredox catalysis under metal-free conditions. This transformation proceeded smoothly in the presence of Rhodamine 6G, affording a series of α,α-difluoro-γ-hydroxyacetamides in moderate to excellent yields. The significant advantages of this protocol are the low-cost photocatalyst, readily available starting materials, synthetic convenience, and wide functional group compatibility.

Arginine GlcNAcylation of Rab small GTPases by the pathogen Salmonella Typhimurium.

Salmonella enterica serovar Typhimurium, an intracellular Gram-negative bacterial pathogen, employs two type III secretion systems to deliver virulence effector proteins to host cells. One such effector, SseK3, is a Golgi-targeting arginine GlcNAc transferase. Here, we show that SseK3 colocalizes with cis-Golgi via lipid binding. Arg-GlcNAc-omics profiling reveals that SseK3 modifies Rab1 and some phylogenetically related Rab GTPases. These modifications are dependent on C-termini of Rabs but independent of the GTP- or GDP-bound forms. Arginine GlcNAcylation occurs in the switch II region and the third α-helix and severely disturbs the function of Rab1. The arginine GlcNAc transferase activity of SseK3 is required for the replication of Salmonella in RAW264.7 macrophages and bacterial virulence in the mouse model of Salmonella infection. Therefore, this SseK3 mechanism of action represents a new understanding of the strategy adopted by Salmonella to target host trafficking systems.

Auto Arginine-GlcNAcylation Is Crucial for Bacterial Pathogens in Regulating Host Cell Death.

Many Gram-negative bacterial pathogens utilize the type III secretion system (T3SS) to inject virulence factors, named effectors, into host cells. These T3SS effectors manipulate host cellular signaling pathways to facilitate bacterial pathogenesis. Death receptor signaling plays an important role in eukaryotic cell death pathways. NleB from enteropathogenic Escherichia coli (EPEC) and SseK1/3 from Salmonella enterica serovar Typhimurium (S. Typhimurium) are T3SS effectors. They are defined as a family of arginine GlcNAc transferase to modify a conserved arginine residue in the death domain (DD) of the death receptor TNFR and their corresponding adaptors to hijack death receptor signaling. Here we identified that these enzymes, NleB, SseK1, and SseK3 could catalyze auto-GlcNAcylation. Residues, including Arg13/53/159/293 in NleB, Arg30/158/339 in SseK1, and Arg153/184/305/335 in SseK3 were identified as the auto-GlcNAcylation sites by mass spectrometry. Mutation of the auto-modification sites of NleB, SseK1, and SseK3 abolished or attenuated the capability of enzyme activity toward their death domain targets during infection. Loss of this ability led to the increased susceptibility of the cells to TNF- or TRAIL-induced cell death during bacterial infection. Overall, our study reveals that the auto-GlcNAcylation of NleB, SseK1, and SseK3 is crucial for their biological activity during infection.

Construction of C(sp2 )-C(sp3 ) Bond between Quinoxalin-2(1H)-ones and N-Hydroxyphthalimide Esters via Photocatalytic Decarboxylative Coupling.

A novel visible-light-driven decarboxylative coupling of alkyl N-hydroxyphthalimide esters (NHP esters) with quinoxalin-2(1H)-ones has been developed. This C(sp2 )-C(sp3 ) bond-forming transformation exhibits excellent substrate generality with respect to both the coupling partners. Of note, a series of 3-primary alkyl-substituted quinoxalin-2(1H)-ones that were difficult to synthesize by previous methods could be obtained in moderate to excellent yields. Additionally, the mild conditions, easy availability of substrates, wide functional group tolerance and operational simplicity make this protocol practical in the synthesis of 3-alkylated quinoxalin-2(1H)-ones.

Superhydrophobic foam prepared from high internal phase emulsion templates stabilised by oyster shell powder for oil-water separation.

In this paper, poly(styrene-divinylbenzene) foams were synthesized using a high internal phase emulsion (HIPE) technique with Span 80 and with 900 °C calcined oyster shell powder as a co-emulsifier, 2,2'-azobisisobutyronitrile (AIBN) as an initiator and deionized water as the dispersing phase. SEM images revealed that the materials possess a hierarchical porous structure of nano/micro size, which resulted in saturated oil adsorption in only half a minute. The dispersing phase amount was investigated for its effect on adsorption. The optimized foams have 24.8-58.3 g g-1 adsorbencies for several organic solvents, and they demonstrated superhydrophobicity and excellent oleophilicity with the water contact angle (WCA) even close to 149° and oil contact angle approaching 0°. Moreover, the foams displayed high oil retention under pressure. The adsorption-centrifugation cycling results indicated high repeatability of the recovered foams. All of these features predicted the potential applications of superhydrophobic foams in oil-water separation.

Selectfluor-induced C(sp2)-O coupling reaction of N-substituted anilines with hydroxylamine derivatives.

A novel avenue of C-O bond construction was facilely achieved via Selectfluor-induced oxygenation of C(sp2)-H bonds of N-substituted anilines by reacting with N-hydroxyphthalimide or N-hydroxymaleimide without any metal catalyst. A variety of N-aryloxyimide derivatives were prepared from N-acyl or sulfonyl anilines in moderate to excellent yields with good functional-group tolerance under mild conditions, which are of great interest in the field of phenol or benzofuran derivative synthesis. Besides, the method is effective on the gram scale, which highlights the practicality of this transformation.

Effect of Body Mass Index on Overall Survival of Pancreatic Cancer: A Meta-Analysis.

Although obesity has been identified as a risk factor for pancreatic cancer, the important question of whether obesity influences the prognosis of pancreatic cancer has not been explicated thoroughly. We therefore performed a meta-analysis to investigate the association between body mass index (BMI) and survival outcomes of patients with pancreatic cancer.Studies that described the relationship between BMI and overall survival (OS) of pancreatic cancer were searched in PubMed, Embase, Ovid, and Cochrane Library Databases from the earliest available date to May 12, 2015. Hazard ratios (HRs) for OS in each BMI category from individual studies were extracted and pooled by a random-effect model. Dose-response meta-analysis was also performed to estimate summary HR and 95% confidence interval (CI) for every 5-unit increment. Publication bias was evaluated by Begg funnel plot and Egger linear regression test.Ten relevant studies involving 6801 patients were finally included in the meta-analysis. Results showed that obesity in adulthood significantly shortened OS of pancreatic cancer patients (HR: 1.29, 95% CI: 1.17-1.41), whereas obesity at diagnosis was not associated with any increased risk of death (HR: 1.10, 95% CI: 0.78-1.42). For every 5-kg/m increment in adult BMI, the summary HR was 1.11 (95% CI: 1.05-1.18) for death risk of pancreatic cancer. However, no dose-response relationship was found in the BMI at diagnosis. Egger regression test and Begg funnel plot both revealed no obvious risk of publication bias.In conclusion, increased adult BMI is associated with increased risk of death for pancreatic cancer patients, which suggested that obesity in adulthood may be an important prognostic factor that indicates an abbreviated survival from pancreatic cancer. More studies are needed to validate this finding, and the mechanism behind the observation should be evaluated in further studies.

Anti-B7-H3 monoclonal antibody ameliorates the damage of acute experimental pancreatitis by attenuating the inflammatory response.

B7-H3, a recently discovered B7 family member, is documented as a regulator in the inflammatory response as well as T cell-mediated immune responses. In this paper, we find that patients with acute pancreatitis revealed overwhelming levels of serum soluble B7-H3 (sB7-H3) associated with the clinical outcomes. Furthermore, B7-H3 protein was marked increased in l-arginine-induced acute experimental pancreatitis. Anti-B7-H3 monoclonal antibody treatment attenuated the proinflammatory cytokine production, downregulated the activation of the NF-κB signaling pathway, and ameliorated the pancreas disruption in l-arginine-induced pancreatitis. In addition, although l-arginine alone failed to induce the production of proinflammatory cytokine and anti-B7-H3 mAb had no effect on the proinflammatory cytokine production of acinar cells, administration of anti-B7-H3 mAb in the coculture model of acinar cells and macrophages stimulated by l-arginine displayed the similar effects. On the whole, B7-H3 participates in the development of acute pancreatitis, and anti-B7-H3 monoclonal antibody ameliorates severity of acute experimental pancreatitis via attenuation of the inflammatory response.

[B7-H3 monoclonal antibody attenuates the inflammation and tissue injury in mice with cerulein-induced acute pancreatitis].

OBJECTIVE: To explore the effect of B7-H3 monoclonal antibody (mAb) on cerulein-induced acute pancreatitis (AP). METHODS: Mice were randomly divided into three groups: control group, AP group and B7-H3 mAb treatment group. AP was induced in mice by intraperitoneal injections of cerulein. B7-H3 mAb was administered to the mice by subcutaneous injection 1 hour before the injections of cerulein. The blood, pancreas and lung tissues of the mice were collected 6, 12 and 24 hours after cerulein induction. Expression of B7-H3 protein was detected in the pancreas tissues of the control and AP groups by Western blotting and immunohistochemistry. Serum activities of amylase and lipase were tested by VITROS 5600 Integrated System. The pancreas wet-dry mass ratio was used to value the edema of pancreas. Pathological changes of pancreas and lung tissues were evaluated by HE staining. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß were detected by ELISA in all groups. RESULTS: The level of B7-H3 protein increased in the pancreas tissues of the AP group after successful induction of cerulein, and reached the peak at 12 hours. Serum activities of amylase and lipase in the AP group were significantly higher than those in the control group, while decreased obviously after the intervention of B7-H3 mAb. H&E staining showed that evident inflammation appeared in pancreas and lung tissues of the AP group, and the inflammation and wet-dry mass ratio were markedly reduced in the treatment group. The levels of proinflammatory factors TNF-α, IL-6 and IL-1ß in the AP group showed a time-dependent increase, and peaked at 12 hours, while in the treatment group were relatively lower. CONCLUSION: B7-H3 is over-expressed in cerulein-induced AP. Anti-B7-H3 mAb can attenuate the inflammation and alleviate the injury of pancreas and lung tissues.

Influence of Fatty Liver on the Severity and Clinical Outcome in Acute Pancreatitis.

Acute pancreatitis (AP) is a common disease in the department of gastroenterology with variable severity, from being mild and self-limited to severe and fatal. The early diagnosis and accurate prediction of AP severity are of great importance. Our primary observation showed that fatty liver (FL) was frequently detected in patients with AP. In this retrospective study, we aimed to evaluate the relation between FL and the severity and outcomes of AP. The medical records of 2671 patients with AP were reviewed retrospectively, and characteristics of AP patients were recorded. FL was assessed by abdominal CT scan, and AP patients were categorized by the occurrence of FL for the analysis. The variation of mortality, clinical severity and the appearance of CT were analyzed between the non-FL group and FL groups. Compared with patients without FL, an obviously higher rate of death and higher frequency of severe AP (SAP) and necrotizing AP (ANP) were observed in patients with FL, as well as the incidence of local complications and systemic complications. Taking obesity into consideration, a higher rate of death and more severe AP were found in patients with FL, no matter whether they were obese or not. Alcoholic fatty liver (AFL) and non-alcoholic fatty liver (NAFL) were also separated for comparison in this study; the incidence of ANP and the clinical severity had no significant difference between the AFL and NAFL groups. In conclusion, FL could influence the severity and clinical outcome and may play a prognostic role in AP. This study is of clinical significance, because few reports have been previously issued on FL and AP.

Recombinant interleukin-1 receptor antagonist attenuates the severity of chronic pancreatitis induced by TNBS in rats.

Chronic pancreatitis (CP) is a common disease in the department of gastroenterology, with the main symptoms of exocrine and/or endocrine insufficiency and abdominal pain. The pathogenic mechanism of CP is still not fully clarified and the aims of treatment now are to relieve symptoms. In this study, we attempted to find a connection between interleukin-1ß (IL-1ß) and interleukin-1 receptor antagonist (IL-1Ra) in trinitrobenzene sulfonic acid (TNBS)-induced chronic pancreatitis, and then the therapeutic effect of recombinant IL-1Ra was also detected in the CP model. Chronic pancreatitis was induced by intraductal infusion of TNBS in SD rats followed by a consecutive administration of rIL-1Ra, and the histological changes and collagen content in the pancreas were measured, as well as the abdominal hypersensitivity. We found that rhIL-1Ra could attenuate the severity of chronic pancreatic injury, modulate the extracellular matrix secretion, focal proliferation and apoptosis, and cellular immunity in TNBS-induced CP. Interestingly, rIL-1Ra could also block the pancreatitis-induced referred abdominal hypersensitivity. In conclusion, IL-1Ra may play a protective role in CP and rIL-1Ra would be a potential therapeutic target for the treatment of CP, while its possible mechanisms and clinical usage still need further investigation.

Analysis of renal impairment in children with Wilson's disease.

BACKGROUND: Since the diverse manifestations of renal impairment appear in different periods of Wilson's disease, misdiagnosis or missed diagnosis is not rare. This study was undertaken to find the clinical features of renal impairment in children with Wilson's disease or hepatolenticular degeneration (HLD). METHODS: Eighty-five children with HLD who had been treated at our department between January 1991 and June 2006 were retrospectively studied. The clinical data of 25 patients with renal impairment were analyzed. RESULTS: In the 85 HLD patients, 34 had renal impairment. Nine of the 34 patients with D-penicillamine treatment were excluded. In the remaining 25 patients, 7 had initiated symptoms of renal impairment, 5 of them with edema, 1 with gross hematuria, and 1 with acute hemolysis and acute renal failure. Twelve of the 25 patients had proteinuria, 14 had hematuria, and 5 had both proteinuria and hematuria. Urine glucose was positive in 4 patients, urine N-acetyl-beta-D-glucosaminidase (NAG) increased in 5, and urine beta2-microglobulin increased in 6. Urine red blood cell (RBC) phase was detected in 7 patients, including glomerular hematuria in 5 patients and non-glomerular hematuria in 2. Blood urea nitrogen and creatinine increased in 1 patient. B-ultrasound revealed bilaterally enlarged kidneys in 3 patients. Kidney biopsy showed diffuse mesangial proliferation and IgA deposit in mesangial region in 1 patient. All of the 25 patients had cornea K-F ring and the level of ceruloplasmin decreased. Six patients had a family history of HLD. CONCLUSIONS: The manifestations of renal impairment with HLD are varied. HLD should be excluded from patients with unexplained renal impairment, while those with HLD should take examinations of the kidney to identify renal impairment. We propose that renal function and urinalysis should be checked regularly in patients receiving treatment of D-penicillamine.