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Yi-Jin Wu,1– 3,* Sa-Sa Zhang,1,* Qin Yin,1 Ming Lei,2 Qi-Hai Wang,4 Wen-Gang Chen,1 Ting-Ting Luo,1 Peng Zhou,5 Cong-Lan Ji4,6 1Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 2Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Vascular Diseases Research Center of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui, 241000, People’s Republic of China; 5School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230000, People’s Republic of China; 6Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Zhou; Cong-Lan Ji, Email zhoupeng@ahtcm.edu.cn; 37709103@qq.comBackground: α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties.Methods: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro.Results: SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes.Conclusion: MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.Graphical Abstract: Keywords: rheumatoid arthritis, mangosteen, metabolism, inflammation, immune

Dan-Dan Wang,1,2,* Chi-Yi He,3,* Yi-Jin Wu,1,2 Liang Xu,4 Chao Shi,1 Opeyemi Joshua Olatunji,5 Jian Zuo,1,6,7 Cong-Lan Ji8 1Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 4Department of Rheumatology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 5Traditional Thai Medical Research and Innovation Center, Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand; 6Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 7Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, People’s Republic of China; 8School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cong-Lan Ji; Jian Zuo, Email 37709103@qq.com; zuojian8178@163.comBackground: Exact roles of many metabolic regulators in rheumatoid arthritis (RA) are to be clarified. This study aimed to further characterize the impacts of silent information regulator 1 (SIRT1) status changes on this disease.Methods: Fluctuation pattern of SIRT1 expression in adjuvant-induced arthritis (AIA) rats was monitored using periodically collected white blood cells. Another bath of AIA rats were treated by SIRT1 agonist resveratrol. Blood from these rats was used to separate monocytes and plasma, which were subjected to polymerase chain reaction (PCR), enzyme linked immunosorbent assay (ELISA), and biochemical analyses. Clinical implication of SIRT1 activation was verified by treating AIA rat monocytes with SIRT1 agonist and overexpression vector in vitro.Results: SIRT1 deficiency occurred in AIA rats, which was accompanied with down-regulation of interleukin 10 (IL-10) and arginase-1 (ARG-1). Resveratrol eased oxidative stress and increased IL-10 production in vivo. Results of ELISA analysis demonstrated that resveratrol attenuated AIA severity in rats. Furthermore, it restored the altered levels of triglyceride, lactate and pyruvate in blood. Resveratrol promoted IL-10 production, and suppressed glycolysis of AIA monocytes cultured in vitro. SIRT1 overexpression similarly reshaped differentiation profile of AIA monocytes, evidenced by changes in metabolism indicators, IL-10 production and AMP-activated protein kinase (AMPK) pathway status. Although overexpressing SIRT1 in normal cells did not affect glycolysis significantly, it attenuated AMPK antagonist-caused abnormality.Conclusion: SIRT1 deficiency is implicated in AIA-related immune abnormality and metabolism alteration. Activating this signaling with resveratrol would impair the inflammatory polarization of monocytes, and consequently ease the severity of RA.Keywords: inflammation, metabolic reprogramming, monocytes, resveratrol, rheumatoid arthritis

Jian Zuo,1– 3,* Meng-Qing Tao,1,3,* Xin-Yue Wu,4 Tian-Tian Jiang,1 Opeyemi Joshua Olatunji,5 Jiyang Dong,4 Jun Han,6 Cong-Lan Ji7 1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4Department of Electronic Science, Xiamen University, Xiamen, 361005, People’s Republic of China; 5Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90112, Thailand; 6Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of China; 7School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun HanDrug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of ChinaEmail hanjun@wnmc.edu.cnCong-Lan JiSchool of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, Anhui, People’s Republic of ChinaEmail 37709103@qq.comBackground: The bark of Securidaca inappendiculata Hassk. is traditionally used for treating inflammatory diseases and bone fractures in China. We have previously validated the xanthone-enriched fraction (XRF) of S. inappendiculata with anti-rheumatic potentials, but mechanism underlying the joints protective effects is still largely unknown.Materials and Methods: The male rats with collagen-induced arthritis (CIA) were treated with XRF. The therapeutic efficacy of XRF was evaluated by arthritis score changes, morphological observation of paws, histological examinations and serological analyses. Protein expression in tissues and cells was investigated by either immunohistochemical or immunoblotting methods, while levels of mRNA expression were investigated by RT-qPCR. Metabolites in serum were detected by LC-MS approach. The joints homogenates were used for analyzing possible targeted genes by genome microarray analyses.Results: Treatment with XRF and methotrexate (MTX) led to significant decrease in arthritis scores, and alleviated deformation of paws in CIA rats. In addition, XRF and MTX reduced circulating TNF-α, IL-1β and IL-17α in the serum and down-regulated TLR4/NF-κB and JNK pathways in joints of CIA rats. Compared to MTX, XRF-loading microemulsion significantly protected joints, which was accompanied by dramatic decrease in MMP3. Differential genes-based KEGG enrichment and metabolomics analysis suggested that XRF reduced fatty acids biosynthesis by regulating PPAR-γ signaling. S inappendiculata-derived 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN) up-regulated PPAR-γ expression in macrophages, but suppressed it in pre-adipocytes in vitro, which was synchronized with SIRT1 changes. Adiponectin production and SCD-1 expression in pre-adipocytes were also decreased. Aside the direct inhibition on MMP3 expression in synovioblast, the presence of XAN in macrophages-pre-adipocytes co-culture system further reinforced this effect.Conclusion: This study revealed the joint protective advantages of the bioactive fraction from S. inappendiculata in CIA rats over MTX, and demonstrated that S. inappendiculata-derived xanthones suppressed the erosive nature of synovioblast acquired under inflammatory circumstances by regulating PPAR-γ signaling-controlled metabolism-immunity feedback.Keywords: peroxisome proliferators-activated receptor gamma, PPAR-γ, energy metabolism, rheumatoid arthritis, metabolomics, macrophage, inflammation

Learning and memory impairment (LMI), a common degenerative central nervous system disease. Recently, more and more studies have shown that Ganoderma lucidum (GL) can improve the symptoms of LMI. The active ingredients in GL and their corresponding targets were screened through TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and BATMAN-TCM (Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine) databases, and the potential LMI targets were searched for through GeneCard (GeneCards Human Gene Database) and DrugBank. Then, we construct a 'main active ingredient-target' network and a protein-protein interaction (PPI) network diagram.The GO (Gene Ontology) functional enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway annotation analysis were performed on the common targets through DAVID (Database for Annotation Visualization and Integrated Discovery) to clarify the potential molecular mechanism of action of active ingredients in GL. The tumor necrosis factor (TNF) protein was verified by Western blot; Twenty one active ingredients in GL and 142 corresponding targets were screened out, including 59 targets shared with LMI. The 448 biological processes shown by the GO functional annotation results and 55 signal pathways shown by KEGG enrichment analysis were related to the improvement of LMI by GL, among which the correlation of Alzheimer's disease pathway is the highest, and TNF was the most important protein; TNF can improve LMI. GL can improve LMI mainly by 10 active ingredients in it, and they may play a role by regulating Alzheimer's disease pathway and TNF protein., (© 2024 The Author(s).)

Ginseng, a highly esteemed herbal medicine, has been utilized over 5000 years, predominantly in Far Eastern countries. Ginseng is categorized into garden ginseng (GG) and ginseng under forest (FG). However, in contrast to FG, excessive intake of GG may lead to potential adverse effects due to disruption of epithelial cell integrity, and the specific population groups that may be at higher risk. In this work, untargeted metabolomics were used to determine the heterogeneity between GG and FG, the data indicates that the content of Ethyl caffeate, Homoorientin, Citric acid and Quinic acid in GG were higher than in FG. Mass spectrometry imaging showed that ethyl caffeate and Homoorientin were concentrated on the brownish yellow exocarp of the primary root. Our experiments demonstrated that excessive exposure to ethyl caffeate and Homoorientin exacerbated the inflammatory response of HUVECs and reduced the expression of cell junctions. This suggest that the compounds causing adverse effects from excessive intake of GG are mainly concentrated in the yellow exocarp of the primary root of GG. These results suggest that untargeted metabolomics coupled with MALDI-MSI can visualize the spatial distribution of endogenous differential molecules of the same herb in different growth environments or developmental stages., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2024. Published by Elsevier B.V.)

The enormous and widespread use of organoboronic acids has prompted the development of innovative synthetic methodologies to meet the demands on structural diversity and functional group tolerance. The existing photoinduced defunctionalization radical borylation, typically focused on the conversion of one C-X bond (X= Br, I, or other leaving group) into only one C-B bond. Herein, we disclose a divergent radical dechloroborylation reaction enabled by dinuclear gold catalysis with visible light irradiation. A wide range of structurally diverse alkyl boronic, α-chloroboronic, and gem-diboronic esters can be synthesized in moderate to good yields (up to 92%). Its synthetic robustness is further demonstrated on a preparative scale and applied to late-stage diversification of complex molecules. The process hinges on a C-Cl bond relay activation in readily available gem-dichloroalkanes through inner-sphere electron transfer, overcoming the redox potential limits of unreactive alkyl chlorides., (© 2024. The Author(s).)

The construction of acyclic, non-adjacent 1,3-stereogenic centers, prevalent motifs in drugs and bioactive molecules, has been a long-standing synthetic challenge due to acyclic nucleophiles being distant from the chiral environment. In this study, we successfully synthesized highly valuable 1,2-bis(boronic) esters featuring acyclic and nonadjacent 1,3-stereocenters. Notably, this reaction selectively produces migratory coupling products rather than alternative deborylative allylation or direct allylation byproducts. This approach introduces a new activation mode for selective transformations of gem-diborylmethane in asymmetric catalysis. Additionally, we found that other gem-diborylalkanes, previously challenging due to steric hindrance, also successfully participated in this reaction. The incorporation of 1,2-bis(boryl)alkenes facilitated the diversification of the alkenyl and two boron moieties in our target compounds, thereby enabling access to a broad array of versatile molecules. DFT calculations were performed to elucidate the reaction mechanism and shed light on the factors responsible for the observed excellent enantioselectivity and diastereoselectivity. These were determined to arise from ligand-substrate steric repulsions in the syn-addition transition state., (© 2023 Wiley-VCH GmbH.)

In recent years, the activation of unactivated alkyl chlorides through light-induced processes has emerged as a promising field in radical chemistry, and has led to new transformations in organic synthesis. Direct utilization of alkyl chlorides as C(sp 3 )-hybridized electrophiles enables the facile construction of carbon-carbon and carbon-heteroatom bonds. Furthermore, recent studies in medicinal chemistry indicate that their presence is associated with high levels of success in clinical trials. This review summarizes the recent advances in the photoinduced activation of unactivated alkyl chlorides and discusses the mechanistic aspects underlying these reactions. We anticipate that this review will serve as a valuable resource for researchers in the field of unactivated chemical bond functionalization, and inspire considerable developments in organic chemistry, drug synthesis, materials science and other related disciplines.

The mechanisms underlying postovulatory oocyte aging (POA) remain largely unknown. The expression of the calcium-sensing receptor (CaSR) in mouse oocytes and its role in POA need to be explored. Our objective was to observe CaSR expression and its role in the susceptibility to activating stimuli (STAS) in POA mouse oocytes. The results showed that, although none of the newly ovulated oocytes were activated, 40% and 94% of the oocytes recovered 19 and 25 h after human chorionic gonadotropin (hCG) injection were activated, respectively, after ethanol treatment. The level of the CaSR functional dimer protein in oocytes increased significantly from 13 to 25 h post hCG. Thus, the CaSR functional dimer level was positively correlated with the STAS of POA oocytes. Aging in vitro with a CaSR antagonist suppressed the elevation of STAS, and cytoplasmic calcium in oocytes recovered 19 h post hCG, whereas aging with a CaSR agonist increased STAS, and cytoplasmic calcium of oocytes recovered 13 h post hCG. Furthermore, the CaSR was more important than the Na-Ca 2+ exchanger in regulating oocyte STAS, and T- and L-type calcium channels were inactive in aging oocytes. We conclude that the CaSR is involved in regulating STAS in POA mouse oocytes, and that it is more important than the other calcium channels tested in this connection.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities., (© 2023 Wiley-VCH GmbH.)

Dinuclear-gold-catalyzed radical difunctionalization of alkyl bromides with 1,7-enynes has been established via dehalogenation and 1,5-HAT processes. This protocol was used to construct, in a facile and efficient manner, a wide range of cyclopenta[ c ]quinolines bearing two quaternary carbon centers with good yields (28 examples, up to 84% yield). The good functional group compatibility and gram-scale preparation ability of the reaction proved its synthetic robustness.

Objective: This study investigated the impacts of SIRT1 activation on rheumatoid arthritis (RA)-related angiogenesis., Methods: HUVECs were cultured by different human serum. Intracellular metabolites were quantified by UPLC-MS. Next, HUVECs and rat vascular epithelial cells under different inflammatory conditions were treated by a SIRT1 agonist resveratrol (RSV). Cytokines and biochemical indicators were detected by corresponding kits. Protein and mRNA expression levels were assessed by immunoblotting and PCR methods, respectively. Angiogenesis capabilities were evaluated by migration, wound-healing and tube-formation experiments. To down-regulate certain signals, gene-specific siRNA were applied., Results: Metabolomics study revealed the accelerated glycolysis in RA serum-treated HUVECs. It led to ATP accumulation, but did not affect GTP levels. RSV inhibited pro-angiogenesis cytokines production and glycolysis in both the cells, and impaired the angiogenesis potentials. These effects were mimicked by an energy metabolism interrupter bikini in lipopolysaccharide (LPS)-primed HUVECs, largely independent of HIF-1α. Both RSV and bikinin can inhibit the activation of the GTP-dependent pathway Rho/ROCK and reduce VEGF production. Abrogation of RhoA signaling reinforced HIF-1α silencing-brought changes in LPS-stimulated HUVECs, and overshadowed the anti-angiogenesis potentials of RSV., Conclusion: Glycolysis provides additional energy to sustain Rho/ROCK activation in RA subjects, which promotes VEGF-driven angiogenesis and can be inhibited by SIRT1 activation., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Taking straws of corn, wheat, and millet as raw materials, we pretreated them with alkaline hydrogen peroxide, and then hydrolyzed by cellulase and xylanase. We selected the total sugar content in the hydrolysate as the indicator to evaluate the hydrolysis of the straws from three crop species, and further optimized the conditions. Then, the hydrolysates of three types of crop straws were used as carbon source for Chlorella sorokiniana culture to assess their effects on microalgal cultivation. The results showed that the optimal hydrolysis conditions for the three crop straws were identified as solid-liquid ratio of 1:15, temperature of 30 ℃, and treatment time of 12 h. Under such optimal condition, the total sugar contents increased up to 1.677, 1.412, and 1.211 g·L -1 in the corn, millet and wheat straw hydrolysate, respectively. The hydrolysates from the three crop straw could significantly increase both algal biomass and lipid content of C. sorokiniana . Corn straw hydrolysate had the best effect, with high levels of algal biomass (1.801 g·L -1 ) and lipid content (30.1%). Therefore, we concluded that crop straw hydrolysates as carbon source could significantly promote microalgal biomass and lipid enrichment. The results could lay the foundation for the efficient conversion and utilization of straw lignocellulose raw materials, provide new knowledge for the resource utilization of agricultural wastes, as well as the theoretical basis for the efficient cultivation of microalgae using crop straw hydrolysates.

We report the first general and practical method for the addition of aryl halides and alkynes to norbornenes with palladium catalysis. Norbornenes have been used as the unsaturated acceptors of aryl and alkynyl groups to construct saturated bridged C-C bonds. The combination of Pd(OAc) 2 /PCy 3 HBF 4 has been identified as the optimal system promoting difunctionalization of norbornenes via the C-X/C-H bond cleavage and highly selective C(sp 3 )-C(sp 2 )/C(sp 3 )-C(sp) bond formation. Broad substrate scope and excellent functional group tolerance have been achieved to show the high efficiency of this approach. Mechanism studies based on experiments and DFT have been performed to gain insights into the catalytic mechanism.

Scope: This study investigates the impacts of lard and related fatty acids intake on rheumatoid arthritis (RA) animal models., Method and Results: Collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) are induced in SD rats and C57 BL/6 mice respectively, which are fed by lard-rich diet (LRD) for 42 days with intake restriction or not. AIA SD rats are treated by representative fatty acids for 30 days. Body weight, arthritis score, and metabolic profile are periodically recorded. Monocyte distribution, cytokine/metabolites levels, gene expression, and tissue damages are investigated by flow cytometry, ELISA, colorimetry, PCR, and histological methods. After being treated by fatty acids in vitro, THP-1 monocytes and the corresponding medium are collected for ELISA, PCR, immunoblotting, and reporter gene assays. Irrespective of intake amounts, LRD decreases inflammatory cytokines and inhibits glycolysis in all rheumatic rodents. Furthermore, it alters monocyte distribution and promotes PPAR-γ expression in AIA mice. Overall evidences show that both saturated (SF) and unsaturated fatty acids (USF) from lard can attenuate inflammation by activating PPAR-γ. Silencing PPAR-γ abrogates their anti-inflammatory effects in vitro. Besides, SF can stimulate TLR4/NF-κB pathway., Conclusion: Lard consumption is beneficial for active inflammatory arthritis recovery. Even SF can activate PPAR-γ and consequently attenuate inflammation., (© 2022 Wiley-VCH GmbH.)

Based on network pharmacology and in vivo experiment, this study explored the therapeutic effect of Tetrastigma hemsle-yanum(SYQ) on sepsis and the underlying mechanism. The common targets of SYQ and sepsis were screened out by network pharmacology, and the "SYQ-component-target-sepsis" network was constructed. The protein-protein interaction(PPI) network was established by STRING. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were performed based on DAVID to predict the anti-sepsis mechanism of SYQ. The prediction results of network pharmacology were verified by animal experiment. The network pharmacology results showed that the key anti-sepsis targets of SYQ were tumor necrosis factor(TNF), interleukin(IL)-6, IL-1β, IL-10, and cysteinyl asparate specific proteinase 3(caspase-3), which were mainly involved in Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappaB(NF-κB) signaling pathway. The results of animal experiment showed that SYQ can decrease the content of C-reactive protein(CRP), procalcitonin(PCT), lactate dehydrogenase(LDH), IL-6, TNF-α, and IL-1β, increase the content of IL-10, and down-regulate the protein levels of Bcl-2-associa-ted X(Bax)/B-cell lymphoma 2(Bcl2), cleaved caspase-3, TLR4, MyD88, and p-NF-κB p65/NF-κB p65. In summary, SYQ plays an anti-inflammatory role in the treatment of sepsis by acting on the key genes related to inflammation and apoptosis, such as TNF-α, IL-6, IL-lβ, IL-10, Bax, Bcl2, and cleaved caspase-3. The mechanism is the likelihood that it suppresses the TLR4/MyD88/NF-κB signaling pathway, which verifies relative prediction results of network pharmacology.

The α-methylene-γ-lactam offers promise as a complementary warhead for the development of targeted covalent inhibitors. However, an understanding of the factors governing its electrophilic reactivity is needed to promote the development of lead compounds utilizing this motif. Herein we synthesize a series of N -aryl-substituted α-methylene-γ-lactams installed within the framework of a bioactive guaianolide analog. To determine the effects of the guaianolide structure on the electrophilic reactivity, these compounds were reacted with glutathione under biomimetic conditions, and the rate constants were measured. A linear free-energy relationship was observed with the Hammett parameter of the N -aryl group within the cis - or trans -annulated isomeric series of compounds. However, the trans -annulated compounds exhibited a ca. 10-fold increase in reactivity relative to both the cis -annulated compounds and the corresponding N -arylated 3-methylene-2-pyrrolidinones. Density functional theory calculations revealed that the reactivity of the trans -annulated stereoisomers is promoted by the partial release of the ring strain of the fused seven-membered ring in the thio-Michael addition transition state.

Background Context: Anterior controllable antedisplacement and fusion (ACAF) is a novel surgical technique for the treatment of ossification of the posterior longitudinal ligament (OPLL) but the surgical learning curve for this technique has not been previously characterized., Purpose: The aim of this study was to quantify a surgeon's learning curve for ACAF and the effect of surgeon experience on postoperative outcomes., Study Design: Prospective study of a single institution and single surgeon experience with ACAF surgery., Patient Sample: A total of 70 consecutive patients with OPLL undergoing ACAF surgery by a single, non-ACAF trained surgeon between 2017 and 2020 were analyzed., Outcome Measures: Intraoperative and postoperative outcomes (blood loss, operative time, errors of surgical procedure, length of hospital stay, Japanese Orthopedic Association (JOA) scoring system, and surgical complications) were assessed., Methods: We prospectively reviewed the first 70 ACAF procedures between 2017 and 2020 performed by a single, non-ACAF trained surgeon. The function relationship between the operative time and case number was fitted using a locally weighted scatterplot smoothing (LOESS) plot. Spearman's correlation analysis was performed to determine factors affecting the operative time. The operative time-related learning curve for ACAF was established and difficulty of each procedure was assessed using a cumulative sum (CUSUM) model. The association between the specific errors of surgical procedures and surgeon experience was further analyzed. A modified CUSUM model was also used to establish the surgical procedure-related learning curve, and thus whether these two learning curves matched with each other was observed. Postoperative outcomes in relation to surgeon experience was compared using a Wilcoxon rank sum test and Chi-squared test., Results: Operative time presented a specific pattern of fewer patient-dependent changes as the case number increased. Spearman's correlation analysis showed the operative time was more affected by the case number (r=-0.73) than the complexity of condition and number of levels hoisted. The operative time-related CUSUM model identified the early (first 29 cases) and late phase (late 41 cases) of the learning process, which was also confirmed by a modified CUSUM model based on surgical procedure. The critical point of the CUSUM model for bilateral osteotomies was at case number 29, and time reduction after the early phase was approximately 34 minutes. Length of hospital stay and blood loss were less during the late phase than during the early phase (p<.05). Although no significant difference was observed in postoperative JOA scores between two phases, patients in the late phase obtained higher recovery rates of neurologic function than those in the early phase (p<.01). There was significant difference in the number of specific errors between the two phases (p=.02). There were no significant differences in overall complication rates between two phases, but a higher incidence of certain complications caused by specific errors was observed in the early phase (p=.02), including CSF leakage, C5 palsy and incomplete decompression., Conclusions: We described, for the first time, a detailed learning curve for ACAF surgery. About 29 cases were needed to achieve mastery of ACAF. Once mastered, the surgeon could deal with various OPLL presentations in a universal way regardless of condition complexity and number of surgical levels. Bilateral osteotomies were the most difficult part of ACAF and produced the greatest reduction in time after mastery. We found a close association between specific errors of surgical procedure for ACAF and surgeon experience. Furthermore, certain complications caused by these errors should be on the alert during the early phase of learning ACAF, including CSF leakage, C5 palsy and incomplete decompression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In 2019, the rate of primary tooth caries rate among 1 598 preschool children in Shinan District and Shibei District of Qingdao was 59.4%. The multivariate logistic regression model showed that compared with children ≤ 2 years old with history of iron deficiency anemia (IDA), suffering IDA, breastfeeding to 2 years old and no tooth melanin, children ≤ 2 years old without history of IDA, not suffering IDA, breastfeeding to less than 2 years old and heavy tooth melanin had a lower risk of primary tooth caries, with OR ( 95%CI ) values about 0.328 (0.197-0.549), 0.354 (0.208-0.603), 0.636 (0.437-0.926) and 0.301 (0.143-0.635), respectively.

Background: KIF23 is a member of kinesin family, recent researches indicate KIF23 plays an important role in the proliferation and migration of malignant cancer cells. While the function and specific molecule mechanism of KIF23 in triple negative breast cancer remains unclear., Methods: QRT-PCR and immunohistochemistry were conducted to analyze expression of KIF23 in triple negative breast cancer tissues and paired paracancer tissues. CCK-8 assay, colony formation assay, wound healing assay and transwell assay were applied for exploring phenotype changing of triple negative breast cancer cell lines MDA-MB-231 and BT549 after siRNA-induced knockdown of KIF23. Several bioinformatic databases were used for predicting miRNAs that combing with KIF23 mRNA and verified by dual luciferase reporter assay. Western blot assay was performed to explore downstream signaling pathway of KIF23., Results: KIF23 was overexpressed in triple negative breast cancer, knockdown of KIF23 by siRNA inhibited proliferation and migration of TNBC cell lines MDA-MB-231 and BT549. Mechanistically, knockdown of KIF23 resulted in the suppression of Epithelial-Mesenchymal Transition. Meanwhile, miR-195-5p was downregulated in TNBC, and dual luciferase reporter assay indicated miR-195-5p could combine with 3'UTR of KIF23 thus promoting degradation of KIF23., Conclusions: KIF23 is a potential oncogene in triple negative breast cancer, miR-195-5p could combine with 3'UTR of KIF23. Our study reveals a new sight into triple negative breast cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-19). The authors have no conflicts of interest to declare., (2021 Gland Surgery. All rights reserved.)

Cooperative bimetallic catalysis is a fundamental approach in modern synthetic chemistry. We report bimetallic cooperative catalysis for the direct decarbonylative heteroarylation of ubiquitous carboxylic acids via acyl C-O/C-H coupling. This novel catalytic system exploits the cooperative action of a copper catalyst and a palladium catalyst in decarbonylation, which enables highly chemoselective synthesis of important heterobiaryl motifs through the coupling of carboxylic acids with heteroarenes in the absence of prefunctionalization or directing groups. This cooperative decarbonylative method uses common carboxylic acids and shows a remarkably broad substrate scope (>70 examples), including late-stage modification of pharmaceuticals and streamlined synthesis of bioactive agents. Extensive mechanistic and computational studies were conducted to gain insight into the mechanism of the reaction. The key step involves intersection of the two catalytic cycles via transmetallation of the copper-aryl species with the palladium(II) intermediate generated by oxidative addition/decarbonylation., (© 2021 Wiley-VCH GmbH.)

Background: Thoracic ossification of the ligamentum flavum (OLF) is a major cause of thoracic myelopathy, which is often accompanied by multiple segmental stenosis or other degenerative spinal diseases. However, in the above situations, it is difficult to determine the exact segment responsible. The objective of this study was to analyze three-dimensional (3D) radiological parameters in order to establish a novel diagnostic method for discriminating the responsible segment in OLF-induced thoracic myelopathy, and to evaluate its superiority compared to the conventional diagnostic methods., Methods: Eighty-one patients who underwent surgery for thoracic myelopathy caused by OLF from 2016 to 2020 were enrolled in this study as the myelopathy group, and 79 patients who had thoracic OLF but displayed no definite neurological signs from 2018 to 2020 were enrolled as the non-myelopathy group. We measured the one-dimensional (1D), two-dimensional (2D), and 3D radiological parameters, calculated their optimal cutoff values, and compared their diagnostic values., Results: Significant differences were observed in the 1D, 2D, and 3D radiological parameters between the myelopathy and non-myelopathy groups (P<0.01). As a 3D radiological parameter, the OLF volume (OLFV) ratio (OLFV ratio = OLFV/normal canal volume × 100%) was the most accurate parameter for diagnosing OLF-induced thoracic myelopathy, with a diagnostic coincidence rate of 88.1%. We also found that an OLFV ratio of 26.3% could be used as the optimal cutoff value, with a sensitivity of 87.7% and a specificity of 88.6%. Moreover, the OLFV ratio [area under the curve (AUC): 0.92, 95% confidence interval (CI): 0.86-0.95] showed a statistically higher diagnostic value than the 1D and 2D parameters (AUC: 0.75, 95% CI: 0.67-0.81; AUC: 0.84, 95% CI: 0.77-0.89, respectively) (P<0.05). Pearson correlation analysis illustrated that the OLFV ratio was significantly negatively correlated with preoperative modified Japanese Orthopedic Association (mJOA) score (r=-0.73, 95% CI: -0.81 to -0.60, P<0.01)., Conclusions: Our results demonstrate the superiority of the OLFV ratio over the conventional 1D and 2D computed tomography (CT)-based radiological parameters for the diagnosis of OLF-induced thoracic myelopathy. The novel diagnostic method based on the OLFV ratio will help to determine the responsible segment in multi-segmental thoracic OLF or when thoracic OLF coexists with other degenerative spinal diseases. The OLFV ratio also accurately reflects the clinical state of symptomatic patients with thoracic OLF., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-713). The authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Objective: Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China. In this study, we aimed to explore its bioactive constituent which contributes to the anti-inflammatory activity., Methods: Polyphenol-enriched and polyphenol-deprived fractions (PRF and PDF, respectively) were separated from the ethanolic extract by HPD300 macroporous resin-based method, and their anti-inflammatory activities were investigated on a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in rats. The possible mechanism of action in alleviating acute inflammation was studied using RAW264.7 cells., Results: Both Folin-Ciocalteu and 1 H nuclear magnetic resonance (NMR) analyses showed that polyphenolic content in PRF was approximately 10 times higher than that of PDF, and this observation reflected in their antioxidative capacities. PRF but not PDF significantly decreased the level of malondialdehyde, suppressed the expression of nicotinamide phosphoribosyltransferase (NAMPT) protein, and improved the severity of ALI in rats. PRF at 10 μg/mL effectively downregulated the expression of proteins NAMPT, HMGB1, TLR4, and p-p65, and scavenged the intracellular reactive oxygen species (ROS) in LPS-primed RAW264.7 cells. N -acetyl- L -cysteine exhibited similar inhibitory effects on ROS production and NAMPT-mediated TLR4/NF-κB activation in vitro , whereas nicotinamide mononucleotide antagonized all the changes induced by PRF during cotreatments., Conclusion: As an antioxidant, PRF exhibited potent anti-inflammatory activity under both in vivo and in vitro conditions by downregulating NAMPT and TLR4/NF-κB. Accordingly, polyphenols were identified as important bioactive constituents in S. inappendiculata targeting oxidative stress-sensitive pro-inflammatory pathways., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

Gold chemistry has developed extensively in the past decade, and a dozen good reviews have been presented discussing this progress. Few however have paid close attention to the progress in organic synthesis of dinuclear gold-catalysis. A dinuclear gold catalyst is defined here as a gold complex with two gold centers linked by a bidentate ligand. With theoretical analysis and some representative studies in recent years, this comprehensive review highlights the particular properties of dinuclear gold-complexes, especially aurophilic interactions, and systematically summarizes the recent achievements of dinuclear gold-catalyzed coupling reactions, asymmetric catalysis, and photocatalysis, where dinuclear gold catalysts tend to show a greater advantage than the mononuclear gold catalysts.

Purpose: Several studies have been performed using recently developed smartphone-based acoustic analysis techniques. We investigated the effects of septoplasty and turbinoplasty in patients with nasal septal deviation and turbinate hypertrophy accompanied by snoring by recording the sounds of snoring using a smartphone and performing acoustic analysis., Methods: A total of 15 male patients who underwent septoplasty with turbinoplasty for snoring and nasal obstruction were included in this prospective study. Preoperatively and 2 months after surgery, their bed partners or caregivers were instructed to record the snoring sounds. The intensity (dB), formant frequencies (F 1 , F 2 , F 3 , and F 4 ), spectrogram pattern, and visual analog scale (VAS) score were analyzed for each subject., Results: Overall snoring sounds improved after surgery in 12/15 (80%) patients, and there was significant improvement in the intensity of snoring sounds after surgery (from 64.17 ± 12.18 dB to 55.62 ± 9.11 dB, p = 0.018). There was a significant difference in the F 1 formant frequency before and after surgery (p = 0.031), but there were no significant differences in F 2 , F 3 , or F 4 . The change in F 1 indicated that patients changed from mouth breathing to normal breathing. The degree of subjective snoring sounds improved significantly after surgery (VAS: from 5.40 ± 1.55 to 3.80 ± 1.26, p = 0.003)., Conclusion: Our results confirm that snoring is reduced when nasal congestion is improved, and they demonstrate that smartphone-based acoustic analysis of snoring sounds can be useful for diagnosis.

Bacillus laterosporus Bl13 has good antagonistic effect on the pathogen of tomato early blight (TEB) disease. A pot experiment was conducted to investigate the effect and mechanism of B. laterosporus Bl13 against TEB disease by measuring biological traits such as plant height, stem diameter, disease index of TEB, activity of plant defense enzyme in leaves, and microbial diversity and community composition in root area. The results showed that B. laterosporus Bl13 could significantly reduce the disease index of TEB disease incidence, increase the activity of defensive enzymes including polyphenol oxidase (PPO) and peroxidase (POD) in leaves, and reduce the effects of the disease on the aboveground and root growth of tomato. Meanwhile, B. laterosporus Bl13 improved soil microbial community structure in the root zone, by significantly increasing the relative abundance of plant growth-promoting bacteria ( Bacillus and Pseudomonas ) and decreasing that of Olpidium and Haematonectria . The results showed that B. laterosporus Bl13 could enhance plant resistance against TEB disease through improving the activity of defensive enzymes in tomato leaves and increasing the number of beneficial microbes in the root zone.

Securidaca inappendiculata Hassk. is a traditional Chinese anti-rheumatic herbal medicine native to southern China. In this study, we identified a possible TLR4 inhibitor from this plant. General effects of its xanthone-rich fraction (XRF) on inflammation in vitro were investigated by immunoblotting experiments performed on lipopolysaccharides (LPS)-treated RAW264.7 cells, and the possible ligand of TLR4 within was screened out by analyzing chemical composition differences of the XRF containing cell culture medium under different inflammatory circumstances. The interaction between ligand and TLR4 was validated by cellular thermal shift assay (CETSA) and molecular docking simulation, and TLR4/NF-κB pathway status was investigated by immunoprecipitation, ELISA, immunofluorescence, dual-luciferase reporter, and immunoblotting experiments. Treatment with XRF resulted in significant decrease in p-p65 and p-JNK, and the signal accounting for 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN) at 12.5 min with mass of 289.29 was greatly decreased in XRF containing medium after LPS stimulus because of enhanced interaction with increased TLR4. CETSA and molecular docking simulation demonstrated that XAN could bind to TLR4 directly on a smooth region adjacent to its contact interface with MD-2. XAN treatment inhibited the dimerization of TLR4 and transcriptional activity of NF-κB in HEK293T cells and decreased p65 accumulation in nucleus and pro-inflammatory cytokines production in RAW264.7 cells receiving LPS treatment. Overall evidences suggest that XAN could be a selective TLR4 inhibitor with potent anti-inflammatory effects. Also, it indicated that xanthone derivatives could have promising clinical application in many immune-mediated inflammations by acting as TLR4 inhibitors.

Herein, we report a catalyst system for Pd-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of aroyl chlorides with boronic acids to furnish biaryls. This strategy is suitable for a broad range of common aroyl chlorides and boronic acids. The synthetic utility is highlighted in the direct late-stage functionalization of pharmaceuticals and natural products capitalizing on the presence of carboxylic acid moiety. Extensive mechanistic and DFT studies provide key insight into the reaction mechanism and high decarbonylative cross-coupling selectivity.

Securidaca inappendiculata is a xanthone rich medicinal plant that has been used in the treatment of inflammation and autoimmune diseases like rheumatoid arthritis (RA) for centuries; however, the material base and mechanism of action responsible for its anti-arthritis effect still remains elusive. The objective of this study is to evaluate the therapeutic effects of xanthone-enriched extract of the plant against collagen-induced arthritis (CIA) in rats and explore the underlying mechanisms. The xanthone-deprived fraction (XDF) and xanthone-rich fraction (XRF) were obtained by using a resin adsorption coupled with acid-base treatment method, and their chemical composition difference was characterized by UPLC-MS/MS analysis. Effects of the two on CIA were analyzed using radiographic, histological, and immunohistochemical analyses. The results indicated that XRF alleviated joint structures destructions with the higher efficacy than XDF, and decreased levels of TNF-α, IL-6, and anti-cyclic citrullinated peptide antibody in CIA rats significantly. Furthermore, XRF inhibited nicotinamide phosphoribosyl transferase (NAMPT) mediated fat biosynthesis and utilization indicated by clinical evidences and metabonomics analysis, which thereby disrupted energy-metabolism feedback. In addition, Toll-like Receptor 4 and High Mobility Group Protein 1 expressions were downregulated in XRF-treated CIA rats. Collective evidences suggest NAMPT could be an ideal target for RA treatments and reveal a novel antirheumatic mechanism of S. inappendiculata by regulating NAMPT controlled fat metabolism., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Background: Health care-associated meningitis or ventriculitis (HCAMV) is a serious complication in different neurosurgical procedures and is associated with significant morbidity and mortality. We aimed to investigate whether an educational intervention program could reduce the HCAMV incidence in patients undergoing postsurgery external ventricular drainage and wound management., Methods: We enrolled 2,904 patients from the neurosurgery intensive care unit between January 1, 2016 and December 31, 2018. The medical staff undertook an educational program developed by a multidisciplinary team on correct external ventricular drainage insertion and maintenance. The program included a 9-page self-learning module on the HCAMV risk factors and operational improvements. Each participant completed a pre- and posttest on their HCAMV knowledge., Results: We found that 38 of 693 (5.48%) patients presented with infection in the preintervention 9-month period. In the 27-month postintervention period, the proportion of HCAMV incidence dropped by 52.19% (P < .0001) to 58 of 2,211 (2.62%) patients., Conclusions: Educational intervention aimed at the neurosurgery intensive care unit staff could significantly reduce the HCAMV rate, leading to a significant decline in the cost, morbidity, and mortality caused by neurosurgical procedures., (Copyright © 2019 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Snoring and obstructive sleep apnoea (OSA) exhibit multifactorial aetiologies; mouth breathing increases airway obstruction and upper respiratory tract resistance. Of the many published studies, few have evaluated sleeping subjects. We explored how mouth breathing affected the upper respiratory tract anatomy and OSA during sleep., Methods: Eighteen patients with OSA, confirmed via full-night polysomnography, were enrolled in this study. We performed drug-induced sleep endoscopy (DISE) and defined obstruction sites before and after mouth closure using commercial mouth strips. We evaluated obstruction sites in two ways, i.e. by grading obstructions using our DISE grading system and measuring the affected areas. Patients who improved by at least one DISE grade were defined as responders. Areas were measured based on DISE videos analysed using ImageJ software. The apnoea-hypopnoea index (AHI) and body mass index (BMI) were recorded., Results: Based on the DISE grade, 40% (7/18) of patients showed obstruction site improvement. When assessed areally, the mean number of pixels improved significantly at both the retropalatal (p = 0.045) and retrolingual (p = 0.019) levels. However, DISE non-responders exhibited no areal improvements. Responders and non-responders did not differ significantly in terms of AHI or BMI (both p < 0.05)., Conclusions: Mouth closure improves or at least does not lead to further deterioration of the upper airway. Improvements were evident at the retropalatal and especially retrolingual levels. Neither the BMI nor the AHI differed between the two groups. However, responders tended to have a higher AHI than non-responders (39.4 vs. 32.8 events/h).

We isolated bacteria from the phycosphere of Scenedesmus obliques and sequenced 16S rDNAs to establish algae-bacterial co-culture systems. Further, we examined effects of the bacteria on algal growth, and parameters associated with physio-biochemical and oil-producing characteristics of S. obliquus. Seven bacterial strains were isolated, including Micrococcus (strains 1-1, 1-2 and 1-3), Pseudomonas sp. (strains 2-1 and 2-2), Exiguobacterium (strain-3) and Staphylococcus sp. (strain-4). Among them, two bacteria (strain 1-2 and strain 2-1) were characterized as the dominant growth-promoting bacterial strains, which significantly increased algal growth, pigment production, and oil enrichment. After eight days cultivation under microalgal-bacterial (strain 1-2) symbiotic systemat at an initial ratio of 1:10, biomass of S. obliquus was 4.27 g·L -1 , about 46.0% higher than that of the control. The contents of chlorophyll a, chlorophyll b and carotenoids were increased by 12.1%, 16.7% and 25.0%, respectively. Oil content was increased by 14.0% and reached to 25.7%, and the oleic acid content was significantly higher than that of the control and up to 16.4%. When co-cultured with Pseudomonas sp. (strain 2-1) for eight days at an initial ratio of 1:5, algal biomass, chlorophyll a, chlorophyll b and carotenoids contents were higher than that of the control by 47.9%, 16.0%, 17.5% and 19.9%, respectively. The total oil (27.1%) and oleic acid (18.2%) contents were increased by 20.4% and 64.0%, respectively. We concluded that Micrococcus (strain 1-2) and Pseudomonas sp. (strain 2-1) could significantly promote algal growth and increase oil production by their beneficial interaction with S. obliques, which could be potentially used in commercial production of S. obliques.

We describe the direct synthesis of organophosphorus compounds from ubiquitous aryl and vinyl carboxylic acids via decarbonylative palladium catalysis. The catalytic system shows excellent scope and tolerates a wide range of functional groups (>50 examples). The utility of this powerful methodology is highlighted in the late-stage derivatization directly exploiting the presence of the prevalent carboxylic acid functional group. DFT studies provided insight into the origin of high bond activation selectivity and P(O)-H isomerization pathway.

Objective: To analyze the relationship between ABO blood groups and otoacoustic emissions in full-term newborns, including the occurrence of SOAE and the amplitudes of DPOAE. Method: A total of eighty normal hearing female neonates were included in the study, with equal number of participants in each of the ABO blood group. Measurements of SOAE and DPOAE were collected from both ears of all participants. Result: The blood group O subjects showed significantly fewer SOAE occurrences and lower DPOAE amplitudes at 793 Hz, 1 257 Hz and 1 587 Hz than subjects with other three blood groups both in the left and right ears. Conclusion: The full-term neonates with blood group O have lower SOAE occurrence than other three blood group individual. The blood group O individuals have the lowest amplitude at 793 Hz, 1 257 Hz and 1 587 Hz of both ears., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

The biaryl motif is a building block in many drugs, agrochemicals, and materials, and as such it is highly desirable as a synthesis target. The state-of-the-art process for biaryl synthesis from ubiquitous carboxylic acids is decarboxylative cross-coupling involving loss of carbon dioxide (CO 2 ). However, the scope of these methods is severely limited, mainly due to specific substitution required to promote decarboxylation. The present report implements a decarbonylative version with loss of carbon monoxide (CO) that enables to directly engage carboxylic acids in a Suzuki-Miyaura cross-coupling to produce biaryls as a general method with high cross-coupling selectivity using a well-defined Pd(0)/(II) catalytic cycle. This protocol shows a remarkably broad scope (>80 examples) and is performed in the absence of exogenous inorganic bases. In a broader context, the approach shows promise for routine applications in the synthesis of biaryls by carefully controlled decarbonylation of prevalent carboxylic acids., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Palladium-catalyzed Suzuki-Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the first palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides for the synthesis of biaryls through the selective activation of the N-C(O) bond of amides. This new method relies on the precise sequence engineering of the catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a mechanism involving oxidative addition, decarbonylation and transmetallation and provide insight into high N-C(O) bond activation selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki-Miyaura cross-coupling of the amide bond and should enable the design of a wide variety of cross-coupling methods in which palladium rivals the traditional biaryl synthesis from aryl halides and pseudohalides., (This journal is © The Royal Society of Chemistry 2019.)

A new double annulation cascade involving a [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) process was first reported, leading to the generation of unprecedented dibenzoannulated naphtho[2,1- b ]oxecines with good to excellent yields and high stereoselectivity through catalytic scission/recombination of C-C double bonds under the mild conditions. An Y(OTf) 3 -catalyzed three-component reaction of α-alkynyl naphthalen-2-ols with β,γ-unsaturated α-ketoesters enabled direct ring expansion of the naphthalene ring and carbon-carbon double bond cleavage/rearrangement of α-ketoesters to give macrocyclic architectures.

The amide bond is one of the most fundamental functional groups in chemistry and biology and plays a central role in numerous processes harnessed to streamline the synthesis of key pharmaceutical and industrial molecules. Although the synthesis of amides is one of the most frequently performed reactions by academic and industrial scientists, the direct transamidation of tertiary amides is challenging due to unfavorable kinetic and thermodynamic contributions of the process. Herein, we report the first general, mild, and highly chemoselective method for transamidation of unactivated tertiary amides by a direct acyl N-C bond cleavage with non-nucleophilic amines. This operationally simple method is performed in the absence of transition metals and operates under unusually mild reaction conditions. In this context, we further describe the direct amidation of abundant alkyl esters to afford amide bonds with exquisite selectivity by acyl C-O bond cleavage. The utility of this process is showcased by a broad scope of the method, including various sensitive functional groups, late-stage modification, and the synthesis of drug molecules (>80 examples). Remarkable selectivity toward different functional groups and within different amide and ester electrophiles that is not feasible using existing methods was observed. Extensive experimental and computational studies were conducted to provide insight into the mechanism and the origins of high selectivity. We further present a series of guidelines to predict the reactivity of amides and esters in the synthesis of valuable amide bonds by this user-friendly process. In light of the importance of the amide bond in organic synthesis and major practical advantages of this method, the study opens up new opportunities in the synthesis of pivotal amide bonds in a broad range of chemical contexts.

Fractalkine has been reported to play an important role in the pathophysiology of various cardiovascular disorders. This research aims to study the change of soluble fractalkine (sFKN) in plasma level of patients with chronic heart failure (CHF) and evaluate its prognostic value.A total of 96 patients with CHF and 45 healthy subjects were included in this study. The plasma levels of sFKN, brain natriuretic peptide (BNP), and Interleukin-18 (IL-18) were determined by ELISA kits when they were first admitted to the hospital. Left ventricular ejection fraction (LVEF) was measured by echocardiogram. Rehospitalization status within 1 year after the first hospitalization was also recorded.The plasma levels of sFKN, BNP, and IL-18 in patients with CHF were significantly higher than in the control group (P < 0.05). The concentrations of sFKN and BNP were increased with the severity of heart failure classified by NYHA classification (P < 0.05). There were no statistical differences among all CHF subgroups classified by etiology (P > 0.05). Plasma sFKN level in CHF group was positively correlated with BNP (r = 0.441, P < 0.001) and IL-18 (r = 0.592, P < 0.001). Receiver operating characteristic curve analysis showed that area under the curve values of FKN, BNP, and IL-18 were 0.885 (95%CI: 0.810 to 0.960, P < 0.001), 0.889 (95%CI: 0.842 to 0.956, P < 0.001), and 0.878 (95%CI: 0.801-0.954, P < 0.001), respectively. The concentrations of sFKN and BNP were increased in patients readmitted more than once within 1 year (P < 0.05).

Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. Herein, we describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/(ii) catalytic cycle. The method shows a remarkably broad substrate scope, enabling to direct the classical acyl reduction towards selective decarbonylation by a redox-neutral mechanism. The utility of this reaction is highlighted in the direct defunctionalization of pharmaceuticals and natural products, and further emphasized in a range of traceless processes using removable carboxylic acids under mild, redox-neutral conditions orthogonal to protodecarboxylation. Extensive DFT computations were conducted to demonstrate preferred selectivity for the reversible oxidative addition and indicated that a versatile hydrogen atom transfer (HAT) pathway is operable.

A nickel-catalyzed Kumada coupling of aniline derivatives was developed by selective cleavage of aryl C-N bonds under mild reaction conditions. Without preinstallation of an ortho directing group on anilines, the cross-coupling reactions of Boc-protected aromatic amines with aryl Grignard reagents afforded unsymmetric biaryls. Mechanistic studies by DFT calculations revealed that the nickel-mediated C-N bond cleavage is the rate-limiting step.

Errors appeared in the article entitled "Increased Plasma Soluble Fractalkine in Patients with Chronic Heart Failure and Its Clinical Significance" by Cui-Ling Ji, Adnan Nomi, Bin Li, Cheng Shen, Bing-Chun Song, and Jin-Guo Zhang (Vol. 60, No. 3, 701-707, 2019). The affiliations of the authors and the address for correspondence on the bottom of page 701 should be replaced by the following.From the 1 Department of Cardiology II, Affiliated Hospital of Jining Medical University, Jining, China, 2 Teaching and Research Section of International Students, Jining Medical University, Jining, China, and 3 Department of Cardiology IV, Affiliated Hospital of Jining Medical University, Jining, China.Address for correspondence: Jin-Guo Zhang, MD, Department of Cardiology II, Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Jining, Shandong 272100, China.

Decarbonylative borylation of carboxylic acids is reported. Carbon electrophiles are generated directly after reagent-enabled decarbonylation of the in situ accessible sterically-hindered acyl derivative of a carboxylic acid under catalyst controlled conditions. The scope and the potential impact of this method are demonstrated in the selective borylation of a variety of aromatics (>50 examples). This strategy was used in the late-stage derivatization of pharmaceuticals and natural products. Computations reveal the mechanistic details of the unprecedented C-O bond activation of carboxylic acids. By circumventing the challenging decarboxylation, this strategy provides a general synthetic platform to access arylpalladium species for a wide array of bond formations from abundant carboxylic acids. The study shows a powerful combination of experiment and computation to predict decarbonylation selectivity., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To evaluate the diagnostic performance of a new method of combined ultrasound elastography (UE) and thyroid imaging-reporting and data system (TI-RADS) in the differential diagnosis of small thyroid nodules., Methods: Ultrasonography(US), TI-RADS, Elasticity Imaging (EI), Virtual Touch Tissue Imaging (VTI) and Virtual Touch Tissue Quantification (VTQ) features of 142 thyroid nodules (maximum diameter ≤10 mm according to conventional ultrasound measurement) confirmed by surgery or FNA were retrospectively analyzed. Different elastographic methods in small benign and malignant thyroid nodules were compared. The diagnostic efficiency of three adjustment methods of conventional ultrasound TI-RADS classification and ultrasound elastography (VTI and/or VTQ) were compared., Results: The pathological examination showed that 70 thyroid nodules were benign and 72 were malignant. The differential ability of UE to diagnose the small benign and malignant thyroid nodules alone is not better than that of conventional ultrasound TI-RADS classification. The sensitivity of conventional ultrasound TI-RADS classification were higher than that of VTI and equal to VTQ(91.67% vs83.33%、91.67%), while the specificity of VTI was much higher than that of TI-RADS and VTQ(91.43% vs 75.71%、60.00%). The diagnostic sensitivity and specificity of TI-RADS classification plus UE (VTI + VTQ) were 94.44% and 87.14% respectively. TI-RADS classification combined with UE (VTI + VTQ) was the highest diagnostic efficiency., Conclusion: Conventional ultrasound TI-RADS classification is the basis for the diagnosis of small thyroid nodules. The combination of TI-RADS with VTI and VTQ can significantly improve the differential diagnosis of small benign and malignant thyroid nodules. It may provide a new and reliable method for the clinical diagnosis of small thyroid nodules., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Securidaca inappendiculata Hassk. (SI) is a medicinal plant used to treat rheumatoid arthritis (RA) in South China. A substantial amount of fatty oil was isolated from SI (SIF), however little knowledge about its chemical composition and medicinal potentials was obtained. In this study, we analyzed its chemical composition with methyl esterification based GC-MS method, and investigated the therapeutic potentials on adjuvant-induced arthritis (AA) in mice. MTT and western-blot methods were employed to investigate its effects on proliferation rate and protein expressions in MH7A cells, respectively. It was revealed SIF was mainly comprised of saturated and monosaturated fatty acids, and the two predominant compounds were palmitic acid (36.89%) and oleic acid (31.12%). Treatment with SIF at 100 mg/kg resulted in significant alleviation of AA severity in mice, together with reduced synovial hyperplasia and inflammatory infiltration in joints, and decreased levels of sialic acid, malondialdehyde and alkaline phosphatase in serum. Results from immunohistochemical assays hinted the protective effects of SIF on joints were associated to the inhibition on production of some pathological factors in synovium, including IL-1β, TNF-α and MMP-9. SIF inhibited the proliferation of MH7A cells in a concentration dependent manner, and abrogated phosphorylation of p65 in vitro. These evidences collectively suggested SIF could suppress the pathological functions of fibroblast-like synoviocyte, and protect joints from destruction under AA conditions., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Nickel catalysis has shown remarkable potential in amide C⁻N bond activation and functionalization. Particularly for the transformation between ester and amide, nickel catalysis has realized both the forward (ester to amide) and reverse (amide to ester) reactions, allowing a powerful approach for the ester and amide synthesis. Based on density functional theory (DFT) calculations, we explored the mechanism and thermodynamics of Ni/IPr-catalyzed amidation with both aromatic and aliphatic esters. The reaction follows the general cross-coupling mechanism, involving sequential oxidative addition, proton transfer, and reductive elimination. The calculations indicated the reversible nature of amidation, which highlights the importance of reaction thermodynamics in related reaction designs. To shed light on the control of thermodynamics, we also investigated the thermodynamic free energy changes of amidation with a series of esters and amides.

Zearalenone (ZEA) is a natural contaminant existing in food and feed products that exhibits a negative effect on domestic animals' reproduction. Donkeys possess high economic value in China and are at risk of exposure to ZEA. However, few information is available on ZEA-induced toxicity and no report on toxicity in donkeys can be found in scientific literature. We investigated the biological effects of ZEA exposure on donkey granulosa cells (dGCs) by using RNA-seq analysis. ZEA at 10 and 30 μM were administered to GCs within 72 h of in vitro culture. ZEA at 10 μM significantly altered the tumorigenesis associated genes in dGCs. Exposure to 10 and 30 μM ZEA treatment significantly reduced mRNA expression of PTEN , TGF β, ATM , and CDK2 genes, particularly, the ZEA treatment significantly increased the expression of PI3K and AKT genes. Furthermore, immunofluorescence, RT-qPCR, and Western blot analysis verified the gene expression of ZEA-exposed GCs. Collectively, these results demonstrated the deleterious effect of ZEA exposure on the induction of ovarian cancer related genes via the PTEN / PI3K / AKT signaling pathway in dGCs in vitro .

Using an asymmetric tetradentate ligand N-((6-(1H-pyrazol-1-yl)pyridin-2-yl)methylene)benzohydrazide (pypzbeyz), two high-coordinate 3d transition metal compounds [CoII(pypzbeyz)(NO3)2] (1) and [FeII(pypzbeyz)2](BF4)2(CH3CN) (2) have been synthesized and characterized by structural and magnetic measurements. X-ray crystallographic analyses revealed that compound 1 is seven-coordinate with a distorted pentagonal bipyramidal geometry (pseudo-D5h) and compound 2 is eight-coordinate with a triangular dodecahedral geometry (pseudo-D2d). Direct current (dc) magnetic susceptibilities revealed that compound 1 shows easy-plane magnetic anisotropy (D = +29.9 cm-1, E = 0.31 cm-1) and 2 shows easy-axis magnetic anisotropy (D = -6.6 cm-1, E = 0.02 cm-1). Alternating current (ac) magnetic measurements indicate that both compounds exhibit field-induced slow magnetic relaxation behavior. Furthermore, ab initio calculations also demonstrate that compound 1 presents a strong easy-plane magnetic anisotropy and 2 presents an easy-axis magnetic anisotropy, which are further identified by the calculated orientations of the local magnetic axes. These results demonstrate an effective way to achieve the targeted synthesis of high-coordinate 3d SIMs.