Pharmaceuticals

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease with the abnormal accumulation of pro-inflammatory macrophages within the synovial joints. Total flavonoids of Rhizoma Drynariae (TFRD), the major bioactive constituents of the traditional Chinese medical herb Drynariae rhizome, have shown potent activities in treating RA, but their effect and underlying mechanism in modulating macrophage behavior remain unknown. This study aimed to evaluate the therapeutic potential of TFRD in regulating macrophage polarization during RA, and to further elucidate the underlying mechanism. Methods: The therapeutic effects of TFRD were assessed by utilizing a collagen-induced arthritis (CIA) mice model in vivo. A macrophage polarization model was employed to investigate the effect of TFRD on the macrophage pro-inflammatory polarization and glycolytic activity in vitro. Additionally, the role of hypoxia-inducible factor-1α (HIF-1α) in the TFRD-mediated regulation of macrophage glycolysis was examined via plasma transfection. Results: Administration of TFRD significantly reduced the arthritis severity scores and ameliorated joint swelling and bone destruction in CIA mice. The therapeutic efficacy of high-dose TFRD (TFRD-H) was broadly similar to that of MTX in CIA mice. Further, TFRD decreased the proportion of pro-inflammatory macrophages and the expression of HIF-1α within the joints of CIA mice. The in vitro experiments indicated that TFRD inhibited the lipopolysaccharide-induced macrophage pro-inflammatory polarization. Mechanistically, TFRD attenuated glycolytic metabolism and downregulated HIF-1α expression during pro-inflammatory polarization, while HIF-1α overexpression partly reversed these effects. Furthermore, 16S rRNA sequencing analysis revealed the mitigated dysbiosis of the gut microbiota and increased relative abundance of Parabacteroides in CIA mice. Conclusions: These findings indicate that TFRD alleviated RA, which was partly dependent on downregulating pro-inflammatory macrophages and mitigating HIF-1α-associated glycolysis. This study could provide a scientific basis for further research and the clinical use of TFRD.

Background/Objectives: The therapeutic landscape of inflammatory bowel disease (IBD) has evolved, particularly with the expanding availability of biologic and targeted therapies. This study characterized real-world prescribing patterns among patients with newly diagnosed Crohn’s disease (CD) and ulcerative colitis (UC) in Germany. Methods: This retrospective study used the German IQVIA Disease Analyzer database. Patients aged 15–80 years diagnosed with CD or UC between 2015 and 2024, with ≥12 months of follow-up and at least one predefined treatment prescription within 12 months after diagnosis, were included. Prescription patterns were compared by IBD subtype, diagnosis period (2015–2019 vs. 2020–2024), age, and sex. Associations were assessed using multivariable logistic regression. Results: Overall, 10,009 patients were included (CD, n = 3810; UC, n = 6199). Mesalazine remained predominant in UC (89.7% in 2015–2019 vs. 87.9% in 2020–2024), whereas biologics were prescribed more frequently in CD and were more common in the later diagnosis period (CD: 32.2% vs. 54.0%; UC: 14.6% vs. 21.5%). UC was associated with higher odds of mesalazine prescription (OR 15.17) and lower odds of biologic prescription (OR 0.28) compared with CD. The later diagnosis period was associated with higher odds of biologic prescription (OR 2.00) and lower odds of mesalazine (OR 0.67) and thiopurine prescription (OR 0.59). Prescription patterns also differed by age, whereas sex-related differences were limited. Conclusions: Among pharmacologically treated patients with newly diagnosed IBD, prescription patterns differed substantially between diagnosis periods, with more frequent biologic and less frequent thiopurine and mesalazine prescriptions in the later period, particularly in CD. Patterns also differed by IBD subtype and age.

Introduction: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder for which single-target strategies may be insufficient. This study explored a host–microbial multitarget strategy using a CNS-oriented small molecule predicted to engage both human acetylcholinesterase (AChE) and Porphyromonas gingivalis lysine-specific gingipain K (Kgp). Methods: A CNS-focused library of 116,226 compounds was standardized and filtered to 1000 candidates for sequential AChE/Kgp docking. Refined docking, interaction-guided pose analysis, dual-target ranking, and SwissADME predictions were used for prioritization. ADKGP_0026671 was subsequently evaluated in single 100 ns molecular dynamics trajectories for AChE and Kgp, alongside donepezil and KYT-36 reference complexes, followed by MM/PBSA endpoint energy analysis. Results: ADKGP_0026671 showed docking scores of −11.804 kcal/mol for AChE and −7.345 kcal/mol for Kgp, was predicted to be BBB-permeant and not a P-glycoprotein substrate, and contained no PAINS or Brenk alerts. The single MD trajectories showed continued binding-site association and limited protein backbone deviation over the simulated period, although reproducibility cannot be established without independent replicas. MM/PBSA endpoint estimates were negative for AChE (−18.86 kcal/mol) and Kgp (−15.67 kcal/mol), but less favorable than donepezil and KYT-36, respectively. Conclusions: ADKGP_0026671 showed a balanced computational profile across two mechanistically distinct targets, supporting experimental evaluation of a host–microbial dual-target strategy in AD. These findings remain hypothesis-generating and require biochemical validation and replicated simulations.