RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

Current models describe aromatic rings as polar groups based on the fact that benzene and hexafluorobenzene are known to have large and permanent quadrupole moments. This report describes a quantitative study of the interactions between oxygen lone pair and aromatic rings. We found that even electron-rich aromatic rings and oxygen lone pairs exhibit attractive interactions. Free energies of interactions are determined using the triptycene scaffold and the equilibrium constants were determined by low-temperature 1H NMR spectroscopy. An X-ray structure analysis for one of the model compounds confirms the close proximity between the oxygen and the center of the aromatic ring. Theoretical calculations at the MP2/aug-cc-pVTZ level corroborate the experimental results. The origin of attractive interactions was explored by using aromatic rings with a wide range of substituents. The interactions between an oxygen lone pair and an aromatic ring are attractive at van der Waals' distance even with electron-donating substituents. Electron-withdrawing groups increase the strength of the attractive interactions. The results from this study can be only partly rationalized by using the current models of aromatic system. Electrostatic-based models are consistent with the fact that stronger electron-withdrawing groups lead to stronger attractions, but fail to predict or rationalize the fact that weak attractions even exist between electron-rich arenes and oxygen lone pairs. The conclusion from this study is that aromatic rings cannot be treated as a simple quadrupolar functional group at van der Waals' distance. Dispersion forces and local dipole should also be considered.

Background Pancreatic cancer remains one of the most rapidly progressive and deadly malignancies worldwide. Current treatment regimens only result in small improvements in overall survival for patients with this cancer type. CPI-613 (Devimistat), a novel lipoate analog inhibiting mitochondrial metabolism, shows the new hope for pancreatic cancer treatment as an efficient and well-tolerated therapeutic option treated alone or in combination with chemotherapy. Methods Pancreatic cancer cells growing in planar 2D cultures and 3D scaffold were used as research platforms. Cell viability was measured by MTT and alamarBlue, and apoptosis was assessed by JC-1 staining and flow cytometry with Annexin V-FITC/PI staining. The mechanism behind CPI-613 action was analyzed by western blot, transmission electron microscopy, and lipolysis assay kits, in the presence or absence of additional signaling pathway inhibitors or gene modifications. Results CPI-613 exhibits anticancer activity in pancreatic cancer cells by triggering ROS-associated apoptosis, which is accompanied by increased autophagy and repressed lipid metabolism through activating the AMPK signaling. Intriguingly, ACC, the key enzyme modulating lipid metabolism, is identified as a vital target of CPI-613, which is inactivated in an AMPK-dependent manner and influences apoptotic process upon CPI-613. Blockade or enhancement of autophagic process does not increase or blunt apoptosis to CPI-613, but inhibition of the AMPK-ACC signaling significantly attenuates apoptosis induced by CPI-613, suggesting CPI-613-mediated lipid metabolism reduction contributes to its cytotoxicity in pancreatic cancer cells. Conclusions These findings explore the critical role of lipid metabolism in apoptosis, providing new insights into the AMPK-ACC signaling axis in crosstalk between lipid metabolism and apoptosis in CPI-613 treatment.

All it takes is the Aldol Nitrogen containing heterocycles have been assembled by means of unprecedented domino processes, designed to take advantage of diversity assembly via strategically decorated Ugi products. The aldol reaction is the second common denominator which enables sequences of up to 5 steps in one pot producing unique molecular architecture in rapid fashion.