cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity.

Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.

From Stilbenes to carbo-Stilbenes: an Encouraging Prospect.

Beyond previously described carbo-naphthalene and carbo-biphenyl, a novel type of bis-carbo-benzenic molecules is envisaged from the stilbene parent. The synthesis, structure, spectroscopic and electrochemical properties of two such carbo-stilbenes are described at complementary experimental and computational DFT levels. In the selected targets, the bare skeletal carbo-mer of carbo-stilbene is decorated by 8 or 10 phenyl groups, 0 or 2 tert-butyl groups, and 2 n-octyl chains, the later substituents being introduced to compensate anticipated solubility issues. As in the parent stilbene series, isomers of the phenylated carbo-stilbenes are characterized. The cis- and trans-isomers are, however, formed in almost equal amounts and could not be separated by either chromatography or crystallization. Nevertheless, due to a slow interconversion at the NMR time scale (up to 55 °C) the 1H NMR signals of both isomers of the two carbo-stilbenes could be tentatively assigned. The calculated structure of the cis-isomer exhibits a helical shape, consistent with the observed magnetic shielding of phenyl p-CH nuclei residing inside the shielding cone of the facing C18 ring. The presence of the two isomers in solution also gives rise to quite broad UV-vis absorption spectra with main bands at ca 460, 560 and 710 nm, and a significant bathochromic shift for the decaphenylated carbo-stilbene vs the di-tert-butyl-octaphenylated counterpart. Square wave voltammograms do not show any resolution of the two isomers, giving a reversible reduction wave at -0.65 or -0.58 V/SCE, and an irreversible oxidation peak at 1.11 V/SCE, those values being classical for most carbo-benzene derivatives. Calculated NICS values (NICS(1)=-12.5±0.2 ppm) also indicate that the aromatic nature of the C18 rings is not markedly affected by the dialkynylbutatriene (DAB) connector between them.

C-H functionalization of quinoline N-oxides catalyzed by Pd(II) complexes: a computational study.

Pd(II) catalysts, particularly the acetate salt in acetic acid, tended to favor regioselective C-H activation of quinoline N-oxides (QOs) at the C2 position. However, Pd(II)Cl2 was shown to catalyze their C-H activation at C8 and, in the presence of water, C8-H activation was accompanied by the formation of 2-quinolinones. The aim of the DFT study described in this work was to shed light on the complete mechanism of these competing catalytic reactions, when PdCl2 reacts with QO and benzaldehyde in dichloroethane. C-H activation of QO was the first step of the reaction and involved either a metallacycle, with a CQO-Pd(II) σ-bond and a C(8)-H-Pd(II) agostic bond, or an η3-QO complex, with three carbon atoms of the heteroring of QO binding PdCl2. The first situation led to the unusual C8 activation and the second to C2 activation. The σ-metallacycle undergoes C8-H activation and the energy of the TOF determining the transition state to form the product is ∼17 kcal mol-1, while for the reaction through the π-metallacycle (C2-H activation) the corresponding energy is higher (∼29 kcal mol-1) and thus is not competitive under the same conditions. The reaction proceeding through the σ-complex, activating the C8 position, is preferred, in agreement with experimental results. Both reactions involve oxidation of Pd(II) to Pd(IV) and the catalyst is regenerated. When small amounts of water are added to the reaction mixture, C8-H activation (acylation) results from the same σ-metallacycle with the same barrier, but the simultaneous formation of 2-quinolinones is more complicated. It starts with OH- attack at the C2 position, and is followed by the migration of two hydrogen atoms, and the final reductive elimination step ends with Pd(0). The higher barriers for the migration and reoxidation of Pd(0) are associated with the more demanding reaction conditions. The different reactivity of Pd(II)(OAc)2 under analogous conditions is clarified, as it is only capable of forming the above mentioned π-complex and thus of activating the C2 position of QO. This catalyst can preferentially activate the C8-H bond under rather different conditions, including in particular acetic acid medium, as shown by other authors.

Rhodium(III)-catalysed redox neutral alkylation of 3-arylbenzo[d]isoxazoles: easy access to substituted succinimides.

A convenient method for the alkylation of 3-arylbenzo[d]isoxazoles with maleimides under redox-neutral conditions has been developed, giving a series of substituted succinimides in up to 99% yield. This transformation is highly selective to give succinimides, and Heck-type products are successfully avoided. This protocol features 100% atom-economy and broad substrate tolerance, and provides a novel strategy for the synthesis of diverse succinimides and an opportunity for the succinylation of protein medication and for pharmacologists to discover first-in-class drugs.

Transition Metal-Controlled Divergent Annulations of Azomethine Imines with Iodonium Ylides via C-Centered [1,2]-Rearrangement.

Transition metal-controlled divergent annulation reactions of azomethine imines with iodonium ylides via C-centered [1,2]-rearrangement have been developed. The azomethine imino group, as a switchable and transient directing group (DG), underwent intramolecular nucleophilic addition and in situ generated bicyclic diaziridine, which facilitated the C-centered [1,2]-rearrangement and subsequent divergent annulations in the presence of different metal complexes as the catalysts. The benzo[c]chromen-1-one and pyrano[de]isochromene scaffolds could be independently constructed with Rh(III) and Ru(II), respectively. It was worth noting that the azomethine imino group was employed first as the switchable DG through rearrangement progress.

Rhodium-Catalyzed [4 + 2] Cascade Annulation to Easy Access N-Substituted Indenoisoquinolinones.

An efficient approach for the synthesis of N-substituted indenoisoquinolinones via rhodium(III)-catalyzed C-H bond activation/subsequent [4 + 2] cyclization starting from easily available 2-phenyloxazolines and 2-diazo-1,3-indandiones has been developed. A series of indeno[1,2-c]isoquinolinones were obtained in up to 93% yield through C-H functionalization, followed by intramolecular annulation, elimination, and ring-opening in a "one pot manner" under mild reaction conditions. This protocol features excellent atom- and step-economy and provides a novel strategy for the synthesis of N-substituted indenoisoquinolinones and a chance to study their biological activities.

2-Butyne Biscarbonate as a "Bridge" in Rhodium(III)-Catalyzed [4 + 2] Cyclization and Diels-Alder Reaction.

Described herein is the development of an unprecedented approach to construct multiple heterocycles with high selectivity through Rh(III)-catalyzed two- or three-component cyclization reaction from simple and readily available starting materials: N-methoxybenzamides, 2-butyne biscarbonate, and maleimides. This methodology provides an efficient strategy for the synthesis of diverse and complicated heterocycles in a one-pot manner and displays excellent features of extremely mild reaction conditions, easy operation, excellent regioselectivity, and good functional group compatibility.

cGAS Mediates Inflammation by Polarizing Macrophages to M1 Phenotype via the mTORC1 Pathway.

Cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, plays a crucial role in antiviral immunity, and its overactivation induces excess inflammation and tissue damage. Macrophage polarization is critically involved in inflammation; however, the role of cGAS in macrophage polarization during inflammation remains unclear. In this study, we demonstrated that cGAS was upregulated in the LPS-induced inflammatory response via the TLR4 pathway, and cGAS signaling was activated by mitochondria DNA in macrophages isolated from C57BL/6J mice. We further demonstrated that cGAS mediated inflammation by acting as a macrophage polarization switch, which promoted peritoneal macrophages and the bone marrow-derived macrophages to the inflammatory phenotype (M1) via the mitochondrial DNA-mTORC1 pathway. In vivo studies verified that deletion of Cgas alleviated sepsis-induced acute lung injury by promoting macrophages to shift from the M1 phenotype to the M2 phenotype. In conclusion, our study demonstrated that cGAS mediated inflammation by regulating macrophage polarization through the mTORC1 pathway, and it further provided a potential therapeutic strategy for inflammatory diseases, especially sepsis-induced acute lung injury.

TBAI-Catalysed Formal [4+4]-Cycloaddition: Easy Access to Oxa-Bridged Eight-Membered Heterocycles.

TBAI-catalysed [4+4]-cyclization reaction of anthranils with hydrazones to deliver oxa-bridged eight-membered heterocycles in accepted yields was developed. Preliminary mechanistic studies indicated that the reaction involved the in situ generation of vinyldiazenes from readily available hydrazones followed by an aza-Michael addition of the anthranil substrates onto the vinyldiazenes and subsequent annulation. This transformation involved the formation of two new C-N bonds and C-O bond in one pot, overcoming the synthetic limitations of anthranils in organic chemistry. This strategy benefits from high efficiency and atomic economy with mild reaction conditions.

Perioperative pectoral nerve block type II and postoperative recurrence in breast cancer: a randomized controlled trial.

BACKGROUND: A new technique for analgesia called pectoral nerve block is widely used in surgeries of breast cancer. Pectoral nerve block type II (Pecs II) block has less influence on immunity when compared with general anesthesia method. The purpose of this research is to demonstrate whether Pecs II block has influence on the recurrence of breast cancer after surgical operation. METHODS: 526 breast cancer patients were recruited in this research and randomized into general anesthesia group and general anesthesia with Pecs II block group. Recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) were evaluated for the two groups. RESULTS: Based on the statistical data, only the consumption of remifentanil was dramatically reduced by the performance of Pecs II block when compared with general anesthesia method. The performance of Pecs II block had no significant influence on OS, RFS, and DRFS of breast cancer patients after surgery. ASA physical status III, TNM stage 2 + 3, and mastectomy were proved to have association with lower recurrence-free survival. CONCLUSION: In conclusion, the performance of Pecs II block declined the remifentanil consumption during surgery of breast cancer. Meanwhile, the performance of Pecs II block had no significant influence on the OS, RFS, and DRFS of breast cancer patients after surgical resection.

Lewis Acid-Catalyzed [3 + 2]-Cyclization of Iodonium Ylides with Azadienes: Access to Spiro[benzofuran-2,2'-furan]-3-ones.

A highly regioselective synthesis of spiro[benzofuran-2,2'-furan]-3-ones has been explored via Lewis acid-catalyzed [3 + 2] cyclization of iodonium ylides with azadienes. The acidity of the Lewis acid was significantly strengthened with strong hydrogen bond donors, thereby promoting the enolization isomerization of iodonium ylides for the subsequent cycloaddition. This reaction was compatible with a broad range of substrates under the mild reaction conditions, and efficiently delivered spiro-heterocycles with excellent stereoselectivity.

Effects of Esketamine Combined with Ultrasound-Guided Pectoral Nerve Block Type II on the Quality of Early Postoperative Recovery in Patients Undergoing a Modified Radical Mastectomy for Breast Cancer: A Randomized Controlled Trial.

Purpose: To evaluate the effect of esketamine combined with ultrasound-guided pectoral nerve block type II (Pecs II block) on the quality of early postoperative recovery in patients undergoing a modified radical mastectomy (MRM) for breast cancer. Patients and Methods: A total of 136 female patients undergoing an elective MRM for unilateral breast cancer (UBC) for the first time were randomly divided into the control group (group C, n=68) and the experimental group (PE group, n=68). In group C, sufentanil was used for anesthesia induction and patient-controlled intravenous analgesia (PCIA). Esketamine was used for anesthesia induction and PCIA in the PE group. Ultrasound-guided Pecs II block was performed after anesthesia induction in the two groups. All other anesthetics were administered in the same way. The primary outcome was the 40-item Quality of Recovery (QoR-40) score at discharge. The secondary outcomes were postoperative Observer's Assessment of Alertness/Sedation Scale (OAA/S) scores, time of anesthesia recovery, Numeric Rating Scale (NRS) scores, serum inflammatory cytokines interleukin-10 (IL-10), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß), Hospital Anxiety and Depression Scale (HADS) scores, length of postoperative Postanesthesia Care Unit (PACU) stay, length of postoperative hospital stay and patient satisfaction score. Results: Compared with group C, the PE group had higher QoR-40 scores at discharge (P<0.05), decreased IL-6 levels at 24 h after surgery (P<0.05), lower anxiety and depression scores (P<0.05) and higher patient satisfaction scores at discharge (P<0.05). No significant difference was found in the NRS score postoperatively between the two groups (P>0.05). There was no significant difference in the postoperative OAA/S score, time of anesthesia recovery, length of postoperative PACU and hospital stays between the two groups (P>0.05). Conclusion: Esketamine combined with Pecs II block can be used for anesthesia in MRM for breast cancer, thus, improving patient quality of early postoperative recovery.

Base-promoted cyclization reaction of o-isothiocyanato arylacetylenes and aroylacetonitriles: easy access to benzo[d][1,3]thiazines.

A green and efficient synthesis of benzo[d][1,3]thiazines through a base-promoted cyclization reaction of o-isothiocyanato arylacetylenes with aroylacetonitriles has been developed. This protocol features high step economy and efficiency, and tolerates various functional groups. The reaction was scalable and applied for the post-modification of drugs.

Visible light-induced selenylative spirocyclization of biaryl ynones toward the formation of selenated spiro[5.5]trienones.

A visible-light induced dearomative cascade cyclization of biaryl ynones with diselenides under photocatalyst and external additive-free conditions has been explored, giving a series of selenated spiro[5.5]trienones in moderate to good yields. The Se-Se bond in diselenides could be cleaved to generate arylselenyl radicals under visible light irradiation in the absence of a photocatalyst. This protocol provides a facile and green method for the synthesis of spiro[5.5]trienones.

Cobalt(II)-Catalyzed C-H and N-H Functionalization of 1-Arylpyrazolidinones with Dioxazolones as Bifunctional Synthons.

Dioxazolone has been attractive as an important synthon for a direct C-H amidation through a nitrene intermediate or Curtius rearrangement to form the isocyanate. However, the combination of two reaction models of dioxazolone has not been reported. Herein, a cobalt-catalyzed C-H and N-H functionalization of 1-arylpyrazolidinones with dioxazolones was developed. The dioxazolones acted as an amidated and carboxamidated reagent. Three C-N bonds were formed in a "one-pot" manner, which promoted the requirement of synthetic diversity.

Rh(III)-Catalyzed Synthesis of Indazolo[2,3-a]quinolines: Vinylene Carbonate as C1 and C2 Building Blocks.

A rhodium-catalyzed cyclization of azobenzenes and vinylene carbonate via C-H bond activation to construct indazolo[2,3-a]quinolines has been developed. This protocol offers an efficient method for synthesis of the titled products in good yields with broad functional group tolerance. In this reaction, three C-C bonds and C-N bond are formed in one pot, and vinylene carbonate (VC) acts as C1 and C2 synthons as well as "vinylene transfer" agent and acylation reagent in the construction of target-fused heterocycles. Moreover, the products exhibit favorable fluorescence properties, which indicate their potential application as fluorescent materials and biosensors.

meta-Allylation of Arenes via Ruthenium-Catalyzed Cross-Dehydrogenative Coupling.

A successful example of oxidative meta-dehydrogenative allylation of arenes with alkenes has been developed using Ru(PPh3)3Cl2 as a catalyst and DTBP as an oxidant. In the allylation process, pyrimidines, pyrazoles, and purines, found widely in nucleosides, were effective auxiliary groups. Gram-scale experiments took place smoothly under optimized conditions. Mechanistic studies indicated that ruthenium-catalyzed meta-dehydrogenative allylation was a free-radical process. The allylation process developed herein provides an efficient and practical strategy to prepare versatile meta-allylated arenes.

Easy synthesis of imidazo[1,5-a]indol-3-ones through Rh(III)-catalyzed C-H allenylation/annulation.

A highly efficient and regioselective synthesis of imidazo[1,5-a]indol-3-ones has been developed via a sequential C-H allenylation/annulation starting from easily available N-methoxycarbamoyl indoles and propargyl alcohols, in which the propargyl alcohols served as a C1 synthon. This strategy displays excellent regioselectivity, high atom economy and tolerates a broad substrate scope.

Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is one of the most common causes of death in pediatric malignancies. However, the clinical chemotherapy for T-ALL has been limited by numerous side effects, emphasizing that novel anti-T-ALL drugs are urgently needed. Herein, a series of 2-acyl-1-dimethylaminomethyl-ferrocenes for cancer therapy have been evaluated. Among them, F1 and F3 exhibited potent cytotoxicity against T-ALL cell lines, especially Jurkat cells, with low cytotoxicity for normal cells. Further mechanistic studies revealed that F1 and F3 could induce apoptosis in Jurkat cells by destructing mitochondrial membrane, enhancing reactive oxygen species (ROS) generation, decreasing the Bcl-2/Bax ratio, releasing Cytochrome c, and increasing the expression of Cleaved Caspase-9/-3 and Cleaved PARP. Additionally, F1 and F3 could suppress cell proliferation and arrest the cell cycle at G0/G1 phase through the PI3K/Akt/mTOR signaling pathway by down-regulating the expression of CDK6, Cyclin D1, p-Akt, p-GSK-3ß, p-mTOR, p-p70 S6K, and up-regulating the expression of P21 and P27, which would also be a possible mechanism. Consequently, ferrocene derivatives F1 and F3 could induce apoptosis through a mitochondria-dependent pathway mediated by ROS, and cell cycle arrest at G0/G1 phase via the PI3K/Akt/mTOR signaling pathway in Jurkat cells. The present study provided fundamental insights into the clinical application of F1 and F3 for the treatment of T-ALL.

Metal-Free Sulfonylative Spirocyclization of Indolyl-ynones via Insertion of Sulfur Dioxide: Access to Sulfonated Spiro[cyclopentenone-1,3'-indoles].

A three-component sulfonylative spirocyclization of indolyl ynones with aryldiazonium salts and a sulfur dioxide surrogate of DABCO·(SO2)2 has been developed, providing a range of sulfonated spiro[cyclopentenone-1,3'-indoles] in moderate to good yields. This transformation was initiated by an in situ generated arylsulfonyl radical and proceeded efficiently under metal-free conditions, involving a radical-induced dearomative cascade cyclization accompanied by the insertion of sulfur dioxide. This protocol provides an efficient and convenient method to access sulfonated spiroindolenines, and tolerant various functional groups.