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Obesity and colorectal cancer are global public health issues, with the prevalence of both conditions increasing over the last 4 decades. In the United States alone, the prevalence of obesity is greater than 40%, and this percentage is projected to increase past 50% by 2030. This review focuses on understanding the association between obesity and the risk of colorectal cancer while also highlighting hypotheses about molecular mechanisms underlying the link between these disease processes. We also consider whether those linkages can be disrupted via weight loss therapies, including lifestyle modifications, pharmacotherapy, bariatric surgery, and endobariatrics.

Interest in electrocatalytic bioconjugation reactions has surged, particularly for modifying tryptophan and tyrosine residues in proteins. We used a cost-effective graphite felt electrode and low-current methodology to achieve selective bioconjugation of tryptophan with thiophenols, yielding up to 92%. This method exclusively labeled tryptophan residues and incorporated fluorinated tryptophan for NMR analysis. Eight polypeptides, including lanreotide and leuprorelin, were effectively coupled, demonstrating the method’s versatility and potential for novel diagnostic and therapeutic agents.

Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein–protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83–0.89, P< 1.0 × 10−8). Propensity score–stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68–0.81, P< 1.0 × 10−8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD.

Abstract ID 52622

It was shown previously (J. Am. Chem. Soc.2014, 136, 10846) that bubbling of O2into a solution of FeII(BDPP) (H2BDPP = 2,6-bis[[(S)-2-(diphenylhydroxymethyl)-1-pyrrolidinyl]methyl]pyridine) in tetrahydrofuran at −80 °C generates a high-spin (SFe= 5/2) iron(III) superoxo adduct, 1. Mössbauer studies revealed that 1is an exchange-coupled system, Ĥex=JŜFe·ŜR, where SR= 1/2is the spin of the superoxo radical, of which the spectra were not well enough resolved to determine whether the coupling was ferromagnetic (S= 3 ground state) or antiferromagnetic (S= 2). The glass-forming 2-methyltetrahydrofuran solvent yields highly resolved Mössbauer spectra from which the following data have been extracted: (i) the ground state of 1has S= 3 (J< 0); (ii) |J| > 15 cm–1; (iii) the zero-field-splitting parameters are D= −1.1 cm–1and E/D= 0.02; (iv) the major component of the electric-field-gradient tensor is tilted ≈7° relative to the easy axis of magnetization determined by the MS= ±3 and ±2 doublets. The excited-state MS= ±2 doublet yields a narrow parallel-mode electron paramagnetic resonance signal at g= 8.03, which was used to probe the magnetic hyperfine splitting of 17O-enriched O2. A theoretical model that considers spin-dependent electron transfer for the cases where the doubly occupied π* orbital of the superoxo ligand is either “in” or “out” of the plane defined by the bent Fe–OO moiety correctly predicts that 1has an S= 3 ground state, in contrast to the density functional theory calculations for 1, which give a ground state with both the wrong spin and orbital configuration. This failure has been traced to a basis set superposition error in the interactions between the superoxo moiety and the adjacent five-membered rings of the BDPP ligand and signals a fundamental problem in the quantum chemistry of O2activation.

Electrochemical synthesis in chemical biology is a milder, biocompatible, and environmentally friendly process for constructing novel types of bioconjugated systems. Herein, we report on the development of an indirect electrochemical strategy that allows a trifluoromethyl group to be incorporated into a tryptophan residue. This protocol allowed fluorinated peptides to be produced, thus allowing their characterization by 19F‐NMR. Interestingly, the trifluoromethylation of tryptophan did not appear under conditions of direct electrolysis; instead, as we introduced ferrocene as a mediator to allow indirect electrosynthesis, the desired product could be obtained in 67% isolated yield. Furthermore, various oligopeptides are successfully coupled to the Trp residue selectively. Mechanistic studies involving CV and DFT calculations indicated that the transformation proceeds through the homo‐cleavage of CF3SO2Na via ferrocene‐mediated indirect electrolysis. Subsequently, the addition of a CF3radical allowed the labelled Trp to be incorporated into the corresponding products. This electrochemical protocol provides a new toolkit for the trifluoromethylation of peptides that contain tryptophan. The late‐stage indirect electrochemical‐induced C−H trifluoromethylationof tryptophan‐containing oligopeptides by treating with CF3SO2Na and ferrocene under mild conditions is reported. CV and DFT calculations indicate that this transformation proceeds through the homo‐cleavage of CF3SO2Na via ferrocene‐mediated indirect electrolysis.

Nickel biomimic: A pentadentate ligand, 2,6‐bis(((S)‐2‐(diphenylhydroxymethyl)‐1‐pyrrolidinyl)methyl)pyridine (H2BDPP), was deprotonated and subsequently reacted with [Ni(CH3CN)6](ClO4)2to give Ni(BDPP) (1). A square‐pyramidal NiIIIcomplex, [Ni(BDPP)](PF6) (2), was obtained via oxidation of 1. Complex 2can oxidize O2−into O2and its EPR spectrum is similar to that of the oxidized form of NiSOD.

The late-stage functionalization of N-unprotected indoles can be useful for modifying low-molecular-weight drugs and bioactive peptides. Whereas indole carboxamides are valuable in pharmaceutical applications, the preparation N-(indol-2-yl)amides with similar structures continues to be challenging. Herein we report on visible-light-induced late-stage photoredox C–H amidation with N-unprotected indoles and tryptophan-containing peptides, leading to the formation of N-(indol-2-yl)amide derivatives. N-Unprotected indoles and aryloxyamides that contain an electron-withdrawing group could be coupled directly to eosin Y as the photocatalyst by irradiation with a green light-emitting diode at room temperature. Mechanistic studies and density functional theory calculations indicate that the transformation might proceed through the oxidative C–H functionalization of indole with a PS* to PS•–cycle. This protocol provides a new toolkit for the late-stage modification labeling and peptide–drug conjugation of N-unprotected indole derivatives.