Emerging research links diabetes pathogenesis to epigenetic modifications beyond genetics and metabolism. We read with great interest the study published in World Journal of Diabetes by Sun et al. They investigate leptin (LEP) gene promoter methylation via methylation-specific polymerase chain reaction and serum LEP quantification (enzyme-linked immunosorbent assay) in non-obese Chinese adults with prediabetes/type 2 diabetes (T2DM). It shows progressive promoter methylation decline from normoglycemia to T2DM, strongly inversely correlated with circulating LEP. This letter critically evaluates their findings, contextualizes them in diabetes epigenetics research, and highlights translational value for early risk stratification and precision prevention in non-obese individuals. Briefly, LEP hypomethylation may drive LEP-insulin axis dysfunction (a T2DM hallmark) by disrupting beta-cell function and insulin sensitivity. Key terms: DNA methylation (methylation of cytosine-guanine cytosines, repressing transcription); epigenetics (heritable gene expression changes without DNA sequence alteration).

The hexafluoroisopropoxy group is a unique and underexplored fluoroalkoxy motif featuring distinctive conformational, electronic, and lipophilic properties. Herein, we report a visible-light-induced C-H hexafluoroisopropoxylation of (hetero)arenes employing a bench-stable N-hexafluoroisopropoxy benzotriazole as the hexafluoroisopropoxy radical precursor. This protocol enables the efficient construction of hexafluoroisopropyl aryl ethers under mild conditions, and is compatible with a broad range of aryl and heteroaryl substrates as well as synthetically and pharmacologically relevant functional groups. Mechanistic studies suggest that photoreductive cleavage of the hexafluoroisopropoxylating reagent by the excited photocatalyst generates the & centerdot;OCH(CF3)(2) radical.

During evolution, nicotinic acetylcholine receptors (nAChRs) have diversified in subunit composition and ligand selectivity, enabling a conserved ion channel scaffold to support a broad range of signaling functions beyond classical synaptic transmission. Deg-3/Des-2 is a nematode-specific, calcium-permeable heteromeric alpha-type nicotinic receptor in sensory neurons to mediate chemosensation, nociception, and mechanotransduction, and represents a promising anthelmintic target. Here, we report cryo-electron microscopy structures of Deg-3/Des-2 in its apo, agonist-bound intermediate and agonist-bound open states. Deg-3/Des-2 adopts a 2Deg-3:3Des-2 stoichiometry. Five agonist molecules occupy intersubunit orthosteric sites, driving channel opening primarily through rotational rearrangements of the upper M2 helices that relieve a conserved hydrophobic gate and enable calcium permeation. We further identify a Deg-3-specific N-terminal helix that regulates desensitization and a negatively charged extracellular vestibular helix that governs calcium permeability. Together, these structures reveal how evolutionary tuning of ligand recognition, ion selectivity, and gating within a conserved nicotinic receptor framework.

Herein, we report a palladium-catalyzed domino arylation/dehydrogenative aromatization of acylcyclohexenes to synthesize meta-aryl acetophenone derivatives. This strategy achieves a previously elusive formal meta-C-H arylation of ketones, even with heteroaryl halides. It allows the late-stage introduction of fluorophores and supramolecular motifs, and the robustness is demonstrated by converting biaryl compounds to cumulenes and an AIE fluorescent Na+ probe. Mechanistic investigations revealed a radical process involving an aryl radical as a hydrogen atom transfer reagent.

Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel highly expressed in the skin and intestine. While its roles in itch and skin inflammation are established, the physiological role of TRPV3 in the intestine remains relatively poorly understood. Topical application of a TRPV3 inhibitor, KM-001, has entered phase I clinical trials for the treatment of pruritus; however, its poor metabolic stability limits broader therapeutic application. Here, we show that the KM-001-derivative Colivin has comparable TRPV3-blocking activity, but enhanced metabolic stability and increased oral bioavailability. Cryo-EM and site-directed mutagenesis analyses established that Colivin binds to the vanilloid binding pocket of TRPV3, stabilizing one of two distinct non-conducting conformations. Oral administration of Colivin effectively suppressed DSS-induced ulcerative colitis (UC) in wild-type, but not Trpv3-deficient mice. Collectively, our findings establish TRPV3 inhibition as a novel therapeutic strategy for UC, offer key structural insights into the inhibition mechanism of TRPV3, and provide critical structural insights for the rational design of potent and selective TRPV3 inhibitors.

DNA primases synthesize short primers required for genome replication, yet the mechanism of initial dinucleotide formation remains poorly understood. Here, we investigate the primase encoded by the pRN1 plasmid from the thermoacidophile archaeon Sulfolobus islandicus, a minimal model for primer synthesis. Using nucleotide analogues to slow the reaction, we capture transient intermediates of dinucleotide formation. Structural NMR and modeling reveal that the ancillary domain simultaneously binds the DNA template and two initiating nucleotides. Unexpectedly, only the second nucleotide base-pairs with the template, whereas the first remains unpaired, inducing template-base flipping and linker interaction. This interaction promotes a closed conformation in which the second nucleotide moves from the initiation to the elongation site and the first forms a base pair in the initiation site, positioning both nucleotides for catalysis. These findings reveal a mechanism for template recognition, nucleotide assembly, and proofreading during primer initiation that is likely conserved among primases.