Low-grade inflammation and metabolic syndrome are seen in many chronic diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). Lifestyle interventions which combine different non-pharmacological therapies have shown synergizing effects in improving outcomes in patients with other chronic diseases or increased risk thereof, especially cardiovascular disease. For RA and metabolic syndrome-associated OA (MSOA), whole food plant-based diets (WFPDs) have shown promising results. A WFPD, however, had not yet been combined with other lifestyle interventions for RA and OA patients. In this protocol paper, we therefore present Plants for Joints, a multidisciplinary lifestyle program, based on a WFPD, exercise, and stress management. The objective is to study the effect of this program on disease activity in patients with RA (randomized controlled trial [RCT] 1), on a risk score for developing RA in patients with anti-citrullinated protein antibody (ACPA) positive arthralgia (RCT 2) and on pain, stiffness, and function in patients with MSOA (RCT 3), all in comparison with usual care.We designed three 16-week observer-blind RCTs with a waiting-list control group for patients with RA with low to moderate disease activity (2.6 ≤ Disease Activity Score [DAS28] ≤ 5.1, RCT 1, n = 80), for patients at risk for RA, defined by ACPA-positive arthralgia (RCT 2, n = 16) and for patients with metabolic syndrome and OA in the knee and/or hip (RCT 3, n = 80). After personal counseling on diet and exercise, participants join 10 group meetings with 6-12 other patients to receive theoretical and practical training on a WFPD, exercise, and stress management, while medication remains unchanged. The waiting-list control group receives usual care, while entering the program after the RCT. Primary outcomes are: difference in mean change between intervention and control groups within 16 weeks for the DAS28 in RA patients (RCT 1), the RA-risk score for ACPA positive arthralgia patients (RCT 2), and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score for MSOA patients (RCT 3). Continued adherence to the lifestyle program is measured in a two-year observational extension study.
Chitin represents an abundant source of nitrogenous polysaccharides, making it a suitable feedstock for organonitrogen platform chemicals. In particular, furanic compounds, such as 3-acetamido-5-acetylfuran (3A5AF), can be readily obtained. Furans can be further functionalized using a Diels-Alder (DA) cycloaddition with a variety of dienophiles. Herein, we report on the DA of 3A5AF, dihydroxyethyl acetamidofuran (Di-HAF), and several derivatives, with maleimide dienophiles. The formation of exo and endo isomers was monitored in detail, and reactivity trends were established experimentally. Kinetic modeling allowed us to establish a reaction network that included a hydration side reaction involving specifically the exo isomer which affects the overall endo/exo ratio of the reaction. Carbonyl and alkyl hydroxyl substituents on the furans changed the DA rate significantly and shifted the selectivity from the exo to the endo product. Density functional theory (DFT) calculations revealed that the presence of a hydroxyl group leads to a thermodynamically favored endo isomer, evidenced by a decreased ΔGendo. Stronger hydrogen bonding interactions and van der Waals interaction in HMFA-involved TS are responsible for its lower ΔG⧧ values as evidenced by noncovalent interaction analysis, probably promoting the cycloaddition rate in the HMFA case. The activation strain model revealed that a faster cycloaddition rate can be attributed to lower interaction and distortion energies in the HMFA case. Additionally, it is the orbital interactions and electrostatic attractions that favor the endo addition in the HMFA case, while easier structural distortion possibly causes the exo selectivity for 3A5AF. These findings aid the development of synthetic strategies for complex chiral skeletons containing compounds based on chitin-derived building blocks.
