Oxidative Cascade Reaction of <i>N</i>‑Aryl-3-alkylideneazetidines and Carboxylic Acids: Access to Fused Pyridines

A versatile silver-promoted oxidative cascade reaction of <i>N</i>-aryl-3-alkylideneazetidines with carboxylic acids is reported, providing a very efficient pathway to functionalized fused pyridines. This method allows introduction of fused pyridine ring systems to heterocycles, drugs, and natural products. A mechanistic study revealed that silver salt is essential for the chemo- and regioselective ring expansion, sequential oxidative nucleophilic additions, and oxidative aromatization. This approach represents the first example of the strained <i>N</i>-heterocycles undergoing a cascade reaction with a π bond and a nucleophile together

Baseline data.

<p>The P values with “*”were obtained using Fisher’s Exact Test, whereas the rest were the result of independent samples t-test.</p

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<p>1,25-Dihydroxyvitamin D [1,25(OH)₂D₃] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)₂D₃ protects patients from sepsis, but clinical treatment with 1,25(OH)₂D₃ is rare. In this study, we report that 1,25(OH)₂D₃ treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)₂D₃via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)₂D₃ can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)₂D₃ on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)₂D₃ upon LPS exposure. Together, we provide evidence that 1,25(OH)₂D₃ attenuates LPS-induced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.</p

Consort flow diagram.

<p>Consort flow diagram.</p

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<p>1,25-Dihydroxyvitamin D [1,25(OH)₂D₃] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)₂D₃ protects patients from sepsis, but clinical treatment with 1,25(OH)₂D₃ is rare. In this study, we report that 1,25(OH)₂D₃ treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)₂D₃via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)₂D₃ can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)₂D₃ on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)₂D₃ upon LPS exposure. Together, we provide evidence that 1,25(OH)₂D₃ attenuates LPS-induced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.</p

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<p>1,25-Dihydroxyvitamin D [1,25(OH)₂D₃] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)₂D₃ protects patients from sepsis, but clinical treatment with 1,25(OH)₂D₃ is rare. In this study, we report that 1,25(OH)₂D₃ treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)₂D₃via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)₂D₃ can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)₂D₃ on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)₂D₃ upon LPS exposure. Together, we provide evidence that 1,25(OH)₂D₃ attenuates LPS-induced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.</p

Localization of the acupuncture specific effects by comparing TE5 verum acupuncture (Group A) vs. TE5 sham acupuncture (Group B) and TE5 verum acupuncture (Group A) vs. nonacupoint acupuncture (Group C).

<p>Abbreviation: BA, Brodmann area; Vox, voxel (represents the number of voxels); N/A, not available (means that the peak voxel was out of the BA zone). The BA area marked by “*”was corrected by a neurological physician.</p

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<p>1,25-Dihydroxyvitamin D [1,25(OH)₂D₃] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)₂D₃ protects patients from sepsis, but clinical treatment with 1,25(OH)₂D₃ is rare. In this study, we report that 1,25(OH)₂D₃ treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)₂D₃via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)₂D₃ can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)₂D₃ on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)₂D₃ upon LPS exposure. Together, we provide evidence that 1,25(OH)₂D₃ attenuates LPS-induced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.</p

Differences of seed associated networks between ROIs from the left hemisphere and the right hemisphere.

<p>Full line represents stronger correlation under acupuncture compared with sham acupuncture, whereas the “dash–dot–dot” line represents weaker correlation. Dash line stands for weaker correlation compared with nonacupoint acupuncture (P<0.05, multiple comparison error corrected using Monte Carlo simulation). Regions of the left hemisphere and right hemisphere that had significant differences in correlation with seeds are placed on left side and right side, respectively, and ROIs in the same box are from the same hemisphere.</p

Stimulation and scanning pattern.

<p>Stimulation and scanning pattern.</p