Orally administered neohesperidin attenuates MPTP-induced neurodegeneration by inhibiting inflammatory responses and regulating intestinal flora in mice.

Parkinson's disease (PD), a neurodegenerative disease, is the leading cause of movement disorders. Neuroinflammation plays a critical role in PD pathogenesis. Neohesperidin (Neo), a natural flavonoid extracted from citric fruits exhibits anti-inflammatory effects. However, the effect of Neo on PD progression is unclear. This study aimed to investigate the effects of Neo on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice and its underlying mechanism. Our results indicated that Neo administration ameliorated motor impairment and neural damage in MPTP-injected mice, by inhibiting neuroinflammation and regulating gut microbial imbalance. Additionally, Neo administration reduced colonic inflammation and tissue damage. Mechanistic studies revealed that Neo suppressed the MPTP-induced inflammatory response by inhibiting excessive activation of NF-κB and MAPK pathways. In summary, the present study demonstrated that Neo administration attenuates neurodegeneration in MPTP-injected mice by inhibiting inflammatory responses and regulating the gut microbial composition. This study may provide the scientific basis for the use of Neo in the treatment of PD and other related diseases.

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes.

In contrast to the traditional and widely-used cycloaddition reactions involving at least a π bond component, a [2σ + 2σ] radical cycloaddition between bicyclo[1.1.0]butanes (BCBs) and cyclopropyl ketones has been developed to provide a modular, concise, and atom-economical synthetic route to substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes and core skeleton of a number of terpene natural products. The reaction was catalyzed by a combination of simple tetraalkoxydiboron(4) compound B2pin2 and 3-pentyl isonicotinate. The broad substrate scope has been demonstrated by synthesizing a series of new highly functionalized BCHs with up to six substituents on the core with up to 99% isolated yield. Computational mechanistic investigations supported a pyridine-assisted boronyl radical catalytic cycle.

Catalysis with Diboron(4)/Pyridine: Application to the Broad-Scope [3 + 2] Cycloaddition of Cyclopropanes and Alkenes.

In contrast to the extensive but non-recyclable use of tetraalkoxydiboron(4) compounds as stoichiometric reagents in diverse reactions, this article reports an atom-economical reaction using a commercial diboron(4) as the catalyst. The key to success was designing a catalytic cycle for radical [3 + 2] cycloaddition involving a pyridine cocatalyst to generate from the diboron(4) catalyst and reversibly mediate the transfer of boronyl radicals. In comparison with known [3 + 2] cycloaddition with transition metal-based catalysts, the current reaction features not only metal-free conditions, inexpensive and stable catalysts, and simple operation but also remarkably broadened substrate scope. In particular, previously unusable cyclopropyl ketones without an activating group and/or alkenes with 1,2-disubstitution and 1,1,2-trisubstitution patterns were successfully used for the first time. Consequently, challenging cyclopentane compounds with various levels of substitution (65 examples, 57 new products, up to six substituents at all five ring atoms) were readily prepared in generally high to excellent yield and diastereoselectivity. The reaction was also successfully applied in concise formal synthesis of an anti-obesity drug and building natural product-like complex bridged or spirocyclic compounds. Mechanistic experiments and computational investigation support the proposed radical relay catalysis featuring a pyridine-assisted boronyl radical catalyst. Overall, this work demonstrates the first approach to use tetraalkoxydiboron(4) compounds as catalysts and may lead to the development of new, green, and efficient transition metal-like boron-catalyzed organic reactions.

Conserved Residues in the C-Terminal Domain Affect the Structure and Function of CYP38 in Arabidopsis.

Arabidopsis cyclophilin38 (CYP38) is a thylakoid lumen protein critial for PSII assembly and maintenance, and its C-terminal region serves as the target binding domain. We hypothesized that four conserved residues (R290, F294, Q372, and F374) in the C-terminal domain are critical for the structure and function of CYP38. In yeast two-hybrid and protein pull-down assays, CYP38s with single-sited mutations (R290A, F294A, Q372A, or F374A) did not interact with the CP47 E-loop as the wild-type CYP38. In contrast, CYP38 with the R290A/F294A/Q372A/F374A quadruple mutation could bind the CP47 E-loop. Gene transformation analysis showed that the quadruple mutation prevented CYP38 to efficiently complement the mutant phenotype of cyp38. The C-terminal domain half protein with the quadruple mutation, like the wild-type one, could interact with the N-terminal domain or the CP47 E-loop in vitro. The cyp38 plants expressing CYP38 with the quadruple mutation showed a similar BN-PAGE profile as cyp38, but distinct from the wild type. The CYP38 protein with the quadruple mutation associated with the thylakoid membrane less efficiently than the wild-type CYP38. We concluded that these four conserved residues are indispensable as changes of all these residues together resulted in a subtle conformational change of CYP38 and reduced its intramolecular N-C interaction and the ability to associate with the thylakoid membrane, thus impairing its function in chloroplast.