Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, and as such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables the development of potent and selective sulfonamide-based 17B-HSD13 inhibitors. In order to probe their inhibitory potency in endogenous expression systems like primary human hepatocytes, inhibitors are transformed into synthetic surrogate substrates with distinct selectivity advantages over substrates previously published. Their application to cells endogenously expressing 17B-HSD13 enables quantitative measures of enzymatic inhibition in primary human hepatocytes which has never been reported to date. Application to multiple cellular systems expressing the protective human variants reveals that the most prevalent IsoD variant maintains NAD-dependent catalytic activity towards some but not all substrates, contradicting reports that the truncation results in loss-of-function. Several 17B-HSD13 variants have been identified as protective against NASH/MASH. However the protein's endogenous function is unknown. Here authors describe sulfonamide-based inhibitors and synthetic substrates, then apply to multiple cellular systems revealing that the most prevalent IsoD variant maintains NAD-dependent catalytic activity.
The first total synthesis of the reported structure of ceanothine D, a cyclopeptide alkaloid found in red root, was achieved using a highly convergent synthetic strategy. Highlights of the synthesis include the first concomitant macrocyclization and formation of the unique chiral tertiary alkyl-aryl ether bond with complete regio- and stereo-control in the presence of a sensitive
Corn silk (CS) has long been consumed as a traditional herb in Korea. Maysin is a major flavonoid of CS. The effects of maysin on macrophage activation were evaluated, using the murine macrophage RAW 264.7 cells. Maysin was isolated from CS by methanol extraction, and preparative $C_{18}$ reverse phase column chromatography. Maysin was nontoxic up to $100{\mu}g/ml$, and dose-dependently increased TNF-${\alpha}$ secretion and iNOS production by 11.2- and 4.2-fold, respectively, compared to untreated control. The activation and subsequent nuclear translocation of NF-${\kappa}B$ was substantially enhanced upon treatment with maysin ($1-100{\mu}g/ml$). Maysin also stimulated the phosphorylation of Akt and MAPKs (ERK, JNK). These results indicated that maysin activates macrophages to secrete TNF-${\alpha}$ and induce iNOS expression, via the activation of the Akt, NF-${\kappa}B$ and MAPKs signaling pathways. These results suggest for the first time that maysin can be a new immunomodulator, enhancing the early innate immunity.
A contemporary undergraduate laboratory experiment incorporating parallel microscale experimentation was developed for the well-defined palladium catalyzed Suzuki–Miyaura cross coupling of 4-fluorophenylboronic acid with both 4-chloro- and 4-bromoanisole using 11 diverse phosphine ligands and one ligandless control. This laboratory introduces students to low-barrier high-throughput experimentation (HTE) technique that is widely utilized in both academic and industrial research settings. This experiment compliments current topics discussed in organic chemistry, inorganic chemistry, and organometallic chemistry lecture courses and serves to reinforce the students' understanding of fundamental concepts of transition metal mediated cross-coupling reactions. Students are also exposed to common analytical tools (thin layer chromatography (TLC) and high-pressure liquid chromatography (HPLC)) used in research settings to analyze the corresponding experimental data.
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