RIP1/3-dependent programmed necrosis induces intestinal injury in septic rats.

The regulation of various types of cell death may help to restore the normal physiological function of cells and play a protective role in sepsis. In the current study, we explore the role of programmed cell necrosis in sepsis and the underlying mechanisms. The septic rat model is established by Cecal-ligation and perforation (CLP), and the in vitro model is established by LPS in IEC-6 cells. Our results demonstrate that receptor-interacting protein 1 (RIP1) is significantly upregulated in the ileum of septic rats and LPS-treated IEC-6 cells at both the mRNA and protein levels. Nec-1, an inhibitor of RIP1, reduces the protein levels of RIP1, p-RIP3, and phosphorylated mixed-lineage kinase domain-like (MLKL) (serine 358) and relieves intestinal injury in CLP-induced septic rats with decreased IL-6 and TNF-α levels. The in vitro experiments further reveal that LPS induces the colocalization of RIP1 and RIP3, resulting in the phosphorylation and translocation of MLKL to the plasma membrane in IEC-6 cells. LPS also facilitates ROS production in IEC-6 cells, but this effect is further reversed by Nec-1, si-RIP1 and si-RIP3. Furthermore, LPS-induced necrosis in IEC-6 cells is counteracted by NAC. Thus, we conclude that RIP1/RIP3-dependent programmed cell necrosis participates in intestinal injury in sepsis and may be associated with RIP1/RIP3-mediated ROS.

Synthesis, characterization and in vitro antiproliferative effects of isosteviol derivatives.

Nineteen isosteviol derivatives were designed and synthesized by C-16, C-19 and D-ring modifications of isosteviol. These compounds were screened for their cytotoxic activities against Hela and A549 cells in vitro. Among them, the inhibitory effect of compounds 3b and 16 on Hela cells was comparable to that of the positive control gefitinib, and the compounds 3b (IC50=7.84 ± 0.84 µM) and 7a (IC50=6.89 ± 0.33 µM) exhibited significant cytotoxicity superior to gefitinib (IC50=11.02 ± 3.27 µM) against A549 cells.

Preventive Effect of the Total Polyphenols from Nymphaea candida on Sepsis-Induced Acute Lung Injury in Mice via Gut Microbiota and NLRP3, TLR-4/NF-κB Pathway.

This study aimed to investigate the preventive effects of the total polyphenols from Nymphaea candida (NCTP) on LPS-induced septic acute lung injury (ALI) in mice and its mechanisms. NCTP could significantly ameliorate LPS-induced lung tissue pathological injury in mice as well as lung wet/dry ratio and MPO activities (p < 0.05). NCTP could significantly decrease the blood leukocyte, neutrophil, monocyte, basophil, and eosinophil amounts and LPS contents in ALI mice compared with the model group (p < 0.05), improving lymphocyte amounts (p < 0.05). Moreover, compared with the model group, NCTP could decrease lung tissue TNF-α, IL-6, and IL-1ß levels (p < 0.05) and downregulate the protein expression of TLR4, MyD88, TRAF6, IKKß, IκB-α, p-IκB-α, NF-κB p65, p-NF-κB p65, NLRP3, ASC, and Caspase1 in lung tissues (p < 0.05). Furthermore, NCTP could inhibit ileum histopathological injuries, restoring the ileum tight junctions by increasing the expression of ZO-1 and occludin. Simultaneously, NCTP could reverse the gut microbiota disorder, restore the diversity of gut microbiota, increase the relative abundance of Clostridiales and Lachnospiraceae, and enhance the content of SCFAs (acetic acid, propionic acid, and butyric acid) in feces. These results suggested that NCTP has preventive effects on septic ALI, and its mechanism is related to the regulation of gut microbiota, SCFA metabolism, and the TLR-4/NF-κB and NLRP3 pathways.

Palladium-catalyzed Heck/aminocarbonylation of alkene-tethered carbamoyl chlorides with nitro compounds for the synthesis of carbamoyl-substituted oxindoles.

A straightforward and efficient approach for the synthesis of carbamoyl-substituted oxindoles has been developed via a palladium-catalyzed Heck cyclization and reductive aminocarbonylation reaction of alkene-tethered carbamoyl chlorides with nitro compounds. The reaction showed good compatibility toward versatile functional groups, and both nitroarenes and nitroalkanes were well tolerated. Using Mo(CO)6 as a solid CO source, without external reductants, a broad range of carbamoyl-substituted oxindoles were obtained in moderate to high yields.

Palladium-catalyzed cascade Heck-type cyclization and reductive aminocarbonylation for the synthesis of functionalized amides.

A palladium-catalyzed Heck/carbonylative cyclization process has been explored for the synthesis of functionalized amides. By using nitroarenes as readily accessible nitrogen sources, a variety of amide products were obtained in moderate to excellent yields with good functional group compatibility. Furthermore, a late-stage modification of a natural molecule is also achieved by this protocol.

Palladium-Catalyzed Reductive Aminocarbonylation of Benzylammonium Triflates with o-Nitrobenzaldehydes for the Synthesis of 3-Arylquinolin-2(1H)-ones.

A palladium-catalyzed straightforward procedure for the synthesis of 3-arylquinolin-2(1H)-ones has been developed. The synthesis proceeds through a palladium-catalyzed reductive aminocarbonylation reaction of benzylic ammonium triflates with o-nitrobenzaldehydes, and a wide range of 3-arylquinolin-2(1H)-ones was obtained in moderate to good yields with very good functional group compatibility.

Palladium-catalyzed carbonylative cyclization of benzyl chlorides with anthranils for the synthesis of 3-arylquinolin-2(1H)-ones.

An efficient carbonylative procedure for the synthesis of 3-arylquinoin-2(1H)-ones has been established. Through a palladium-catalyzed aminocarbonylation of benzyl chlorides with anthranils, a variety of 3-arylquinoin-2(1H)-one products were obtained in moderate to excellent yields with good functional group tolerance.

Identification and characterization of neutrophil heterogeneity in sepsis.

BACKGROUND: Although the immune function of neutrophils in sepsis has been well described, the heterogeneity of neutrophils remains unclear during the process of sepsis. METHODS: In this study, we used a mouse CLP model to simulate the clinical scenario of patients with sepsis, neutrophil infiltration, abnormal distribution and dysfunction was analyzed. LPS was used to stimulate neutrophils in vitro to simulate sepsis; single-cell gene sequencing technology was used to explore the immunological typing. To explore the immunological function of immunosuppressive neutrophils, PD-L1 knockout neutrophils were cocultured with lymphocytes from wild-type mice. RESULTS: We found that neutrophils presented variant dysfunction at the late stage of sepsis, including inhibition of apoptosis, seriously damaged chemotaxis and extensive infiltration into the tissues. Single-cell RNA sequencing revealed that multiple subclusters of neutrophils were differentiated after LPS stimulation. The two-dimensional spatial distribution analysis showed that Foxp3+ T cells were much closer to Ly-6G than the CD4+ and CD8+ cells, indicating that infiltrated neutrophils may play immunomodulatory effect on surrounding T-regs. Further observations showed that LPS mediates PD-L1 over expression through p38α-MSK1/-MK2 pathway in neutrophils. The subsets of highly expressed PD-L1 exert immunosuppressive effect under direct contact mode, including inhibition of T cell activation and induction of T cell apoptosis and trans-differentiation. CONCLUSIONS: Taken together, our data identify a previously unknown immunosuppressive subset of neutrophils as inhibitory neutrophil in order to more accurately describe the phenotype and characteristics of these cells in sepsis.

A Convenient Palladium-Catalyzed Carbonylative Synthesis of (E)-3-Benzylidenechroman-4-ones.

A convenient palladium-catalyzed carbonylation reaction for the efficient synthesis of (E)-3-benzylidenechroman-4-ones has been developed. Using TFBen as a solid CO source, a range of substituted (E)-3-benzylidenechroman-4-ones were prepared in moderate to good yields with 2-iodophenols and allyl chlorides as the substrates. Additionally, substituted quinolin-4(1H)-ones can also be obtained with 2-iodoaniline as the starting material.

Palladium-Catalyzed Carbonylative Synthesis of Isoindolinones from Benzylamines with TFBen as the CO Source.

A palladium-catalyzed C-H carbonylation of benzylamines for the synthesis of isoindolinone scaffolds has been developed. This protocol is conducted under gas-free conditions by using benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate, furnishing a variety of isoindolinone derivatives in moderate to high yields (up to 95%).

Nickel-Catalyzed Molybdenum-Promoted Carbonylative Synthesis of Benzophenones.

A nickel-catalyzed molybdenum-promoted carbonylative coupling reaction for the synthesis of benzophenones from aryl iodides has been developed. Various substituted diaryl ketones were synthesized in moderate to excellent yields under CO-gas-free conditions. A synergetic effect of both nickel and molybdenum has been observed, which is also responsible for the success of this transformation.

Palladium-catalyzed synthesis of quinolin-2(1H)-ones: the unexpected reactivity of azodicarboxylate.

Quinolin-2(1H)-one is a useful structure unit present in a wide range of natural products and pharmaceuticals. A Pd(ii)-catalyzed synthesis of quinolin-2(1H)-ones from quinoline N-oxides was developed with azodicarboxylates which act as both the activating agent and oxidant. The reaction proceeded under mild conditions and no protection against air and moisture was needed.

Palladium-Catalyzed Carbonylative Transformation of Organic Halides with Formic Acid as the Coupling Partner and CO Source: Synthesis of Carboxylic Acids.

A palladium-catalyzed carbonylative transformation of organic halides with formic acid as the coupling partner to produce carboxylic acids has been developed. With a catalytic amount of DCC as the activator of formic acid, the process can be realized successfully through benzoic formic anhydride as the intermediate. Both vinyl and aryl (pseudo)halides were conveniently transformed into the corresponding acids in good yields.

A general and convenient palladium-catalyzed synthesis of benzylideneindolin-3-ones with formic acid as the CO source.

A general and convenient palladium-catalyzed carbonylative synthesis of 2-benzylideneindolin-3-ones from 2-iodoanilines and arylacetylenes has been developed. With formic acid as the CO source and Ac2O as the activator, a variety of 2-benzylideneindolin-3-ones were obtained in good to excellent yields with exceptional functional group tolerance.

Palladium-catalyzed carbonylative synthesis of benzofuran-2(3H)-ones from 2-hydroxybenzyl alcohols using formic acid as the CO source.

A palladium-catalyzed carbonylative intramolecular synthesis of benzofuran-2(3H)-ones from 2-hydroxybenzyl alcohols has been developed. In this procedure, formic acid was utilized as the CO source, and various benzofuran-2(3H)-one derivatives were obtained in moderate to good yields.

A Convenient Palladium-Catalyzed Reductive Carbonylation of Aryl Iodides with Dual Role of Formic Acid.

Palladium-catalyzed reductive carbonylation of aryl halides represents a straightforward pathway for the synthesis of aromatic aldehydes. The known reductive carbonylation procedures either require CO gas or complexed compounds as CO sources. In this communication, we developed a palladium-catalyzed reductive carbonylation of aryl iodides with formic acid as the formyl source. As a convenient, practical, and environmental friendly methodology, no additional silane or H2 was required. A variety of aromatic aldehydes were isolated in moderate to excellent yields under mild reaction conditions. Notably, this is the first procedure on using formic acid as the formyl source.

The electrocardiographic characteristics of an acute embolism in the pulmonary trunk and the main pulmonary arteries.

OBJECTIVE: Pulmonary embolism (PE) is a common cardiovascular disease that can be easily missed or misdiagnosed. Electrocardiogram (ECG) is valuable in making early diagnoses and performing risk stratification with regard to acute PE. METHODS: A total of 147 hospitalized patients diagnosed with acute PE were enrolled in this study and divided into the following 2 groups: main pulmonary artery trunk or main pulmonary artery (MPA) embolism and lobar artery or remote branch embolism. Electrocardiographic abnormalities associated with acute PE were subsequently identified. RESULTS: Electrocardiographic abnormalities were significantly different between the pulmonary trunk/MPA embolism group and the lobar artery/remote branch embolism group. The incidence of pulmonary trunk/MPA emboli was significantly related to the number of ECG abnormalities (t = -7.086, P = 5.556e-11). Furthermore, the number of ECG abnormalities noted among patients with pulmonary trunk/MPA emboli was 5.276 times greater than the number observed among the lobar artery/remote branch embolism group (P < .001, 95% confidence interval = -6.57 to 3.97). The risk of either moderate or severe right ventricular hypertrophy was increased by 16.18% among patients with either pulmonary trunk or MPA emboli compared with patients with either lobar artery or remote branch emboli (P < .001, 95% confidence interval = -2.76 to 0.876). The correct classification rate was as high as 92.3% when ECG was used to classify the prognosis of PE patients. CONCLUSIONS: The number of ECG abnormalities and the degree of right ventricular hypertrophy as determined via ECG can be used to assess the probability of developing a PE in the pulmonary trunk and MPA. Furthermore, ECGs can assist clinicians with risk stratification.

[Effect of Taohong Qinlian Decoction on HMGB1 in Septic Rat Cardiac Muscle].

OBJECTIVE: To observe the levels of high mobility group box-1 protein (HMGB1), tumor necrosis factor-alpha (TNF-α), IL-6, troponin I (Tn I) release in septic rats, and to explore themechanism of Taohong Qinlian Decoction (TQD) in the treatment of septic myocardial injury. METHODS: A total of 48 healthy male Wistar rats of clean grade were randomly divided into the sham-operation group (Sham), the sepsis model group (CLP), and the TQD treatment group (ZY), 16 in each group. Concen-trations of TNF-α, IL-6, Tn I, and HMGB1 expression were detected in each group at 24 and 48 h after operation. Pathological changes of cardiac muscle were observed under light microscope. RESULTS: Concentrations of TNF-α, IL-6, Tn I and HMGB1 at 24 and 48 h after operation were significantly higher in the CLP group than in the Sham group (P < 0.01). Concentrations of TNF-α, IL-6, Tn I, and HMGB1 at 24 and 48 h after operation were significantly lower in the ZY group than in the CLP group (P < 0.05). Myocardial injury occurred in the CLP and the ZY group under light microscope. And this injury was more severe in the CLP group than in the ZY group. CONCLUSION: TQL could reduce the level of sepsis-related inflammatory cytokines and protect myocardium in septic rats.

A Convenient Palladium-Catalyzed Carbonylative Suzuki Coupling of Aryl Halides with Formic Acid as the Carbon Monoxide Source.

A practical palladium-catalyzed carbonylative Suzuki coupling of aryl halides under carbon monoxide gas-free conditions has been developed. Here, formic acid was utilized as the carbon monoxide source for the first time with acetic anhydride as the additive. A variety of diarylketones were produced in moderate to excellent yields from the corresponding aryl halides and arylboronic acids.