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Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivitynamely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-productsand the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E- or Z-trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D., Author(s): Thach T. Nguyen [1]; Ming Joo Koh [1]; Tyler J. Mann [1]; Richard R. Schrock [2]; Amir H. Hoveyda (corresponding author) [1] Linear E - and Z -trisubstituted alkenes [...]

One shortcoming of olefin metathesis has been that acyclic alkenyl halides could not be generated efficiently and stereoselectively; but now halo-substituted molybdenum alkylidene species are shown to be able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules. Catalytic olefin metathesis Olefins with a halide substituent are a mainstay in synthetic chemistry. However, the scope for the efficient stereoselective synthesis of acyclic alkenyl halides -- a class of compound common that includes many biologically active natural products -- has been limited. Amir Hoveyda and colleagues show here that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and can participate in high-yielding olefin metathesis reactions that produce acyclic 1,2-disubstituted Z-alkenyl halides. Many alkenyl chlorides, bromides and fluorides can be obtained in up to 91% yield and complete Z selectivity., Author(s): Ming Joo Koh [sup.1] , Thach T. Nguyen [sup.1] , Hanmo Zhang [sup.1] , Richard R. Schrock [sup.2] , Amir H. Hoveyda [sup.1] Author Affiliations: (1) Department of Chemistry, [...]

Author(s): Ming Joo Koh [1]; Thach T. Nguyen [1]; Jonathan K. Lam [2]; Sebastian Torker [1]; Jakub Hyvl [2]; Richard R. Schrock [2]; Amir H. Hoveyda (corresponding author) [1] The [...]

Author(s): Xiao Shen [1]; Thach T. Nguyen [1]; Ming Joo Koh [1]; Dongmin Xu [1]; Alexander W. H. Speed [1]; Richard R. Schrock [2]; Amir H. Hoveyda (corresponding author) [1] [...]

Amlexanox is an anti-inflammatory and anti-allergic agent used clinically for the treatment of aphthous ulcers, allergic rhinitis, and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of IkB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1), suppresses a range of diseases or inflammatory conditions, such as obesity-related metabolic dysfunction and type 2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehensively studied. In this study, we investigated the novel therapeutic effect of amlexanox on LPS-induced neuroinflammation in vivo, and intraperitoneal injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as evidenced by ionized calcium-binding adapter molecule 1 (Iba1) immunostaining. Furthermore, amlexanox significantly reduced proinflammatory cytokines and chemokines in LPS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human HMC3 microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demonstrated that the anti-inflammatory action of amlexanox in BV2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In addition, the combination of amlexanox and SPI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a potential therapeutic strategy for neuroinflammation-related diseases., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus (GDM) is linked to the dysregulation of inflammatory markers in women with GDM compared to women without. It is unclear whether the intensity of glycemic control influences these biomarkers. We aimed to assess whether different glycemic targets for women with GDM and compliance influence maternal and infant biomarkers., Methods: Maternity hospitals caring for women with GDM were randomized in the TARGET Trial to tight or less tight glycemic targets. Maternal blood was collected at study entry, 36 weeks' gestation, and 6 months postpartum, and cord plasma after birth. We assessed compliance to targets and concentrations of maternal serum and infant biomarkers., Results: Eighty-two women and infants were included in the study. Concentrations of maternal and infant biomarkers did not differ between women assigned to tighter and less tight glycemic targets; however, concentrations were altered in maternal serum leptin and CRP and infant cord C-peptide, leptin, and IGF in women who complied with tighter targets., Conclusions: Use of tighter glycemic targets in women with GDM does not change the concentrations of maternal and infant biomarkers compared to less tight targets. However, when compliance is achieved to tighter targets, maternal and infant biomarkers are altered., Impact: The use of tighter glycemic targets in gestational diabetes does not result in changes to maternal or cord plasma biomarkers. However, for women who complied with tighter targets, maternal serum leptin and CRP and infant cord C-peptide, leptin and IGF were altered compared with women who complied with the use of the less tight targets. This article adds to the current evidence base regarding the impact of gestational diabetes on maternal and infant biomarkers. This article highlights the need for further research to assess enablers to meet the tighter target recommendations and to assess the impact on relevant biomarkers., (© 2023. The Author(s).)

Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that can lead to terminal respiratory failure. Ultrafine carbonaceous particles, which are ubiquitous in ambient urban and indoor air, are increasingly considered as major contributors to the global health burden of air pollution. However, their effects on the expression of CFTR and associated genes in lung epithelial cells have not yet been investigated. We therefore evaluated the effects of carbon nanoparticles (CNP), generated by spark-ablation, on the human bronchial epithelial cell line 16HBE14o- at air-liquid interface (ALI) culture conditions. The ALI-cultured cells exhibited epithelial barrier integrity and increased CFTR expression. Following a 4-h exposure to CNP, the cells exhibited a decreased barrier integrity, as well as decreased expression of CFTR transcript and protein levels. Furthermore, transcriptomic analysis revealed that the CNP-exposed cells showed signs of oxidative stress, apoptosis and DNA damage. In conclusion, this study describes spark-ablated carbon nanoparticles in a realistic exposure of aerosols to decrease CFTR expression accompanied by transcriptomic signs of oxidative stress, apoptosis and DNA damage., (© 2022. The Author(s).)

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.