Heilongjiang University of Chinese Medicine

Bacterial outer membrane vesicles (OMVs) were previously considered merely as waste products of bacterial metabolism. But its inherent stability, immunogenicity, ability to be highly regulated, and targeting potential are turning them into a platform with revolutionary potential in tumor drug delivery. Tumor remains a major challenge in medicine. Even though traditional therapies are effective to some extent, they are often accompanied by intolerable side effects. Furthermore, conventional treatments have low targeting efficiency, and tumor cells almost always develop resistance to them. OMVs are naturally tiny vesicles released by Gram-negative bacteria. They possess the ability to deliver drugs very efficiently and at the same time stimulate the host immune system. As a result, they can overcome limitations such as poor targeting and drug resistance. OMVs have huge potential not only in tumor therapy but also in the development of vaccines and drug delivery systems. Nevertheless, reviews focusing solely on their role in tumor drug delivery systems are still quite rare. This review thoroughly analyzes the immunological basis of bacterial OMVs, the engineering strategies, and their antitumor applications with a focus on how their innate immunogenicity and highly customizable features can be exploited to develop precision antitumor platforms. It essentially offers a comprehensive and systematic theoretical framework for realizing and elevating the latent use of bacterial OMVs in tumor therapy.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by symptoms such as persistent diarrhea. Shenlingbaizhu Formula (SLBZ), a classical Chinese herbal formula with centuries of clinical application, has long been used to treat such gastrointestinal disorders. This historical efficacy provides a strong ethnopharmacological rationale for investigating its therapeutic potential and underlying mechanisms in UC.

To elucidate the molecular mechanism by which SLBZ ameliorates UC by restoring the intestinal barrier via the sGC-cGMP-PKG signaling pathway.

To systematically investigate the therapeutic effects of SLBZ on UC, we established a dextran sulfate sodium (DSS)-induced colitis model in 57BL/6 mice. Comprehensive evaluations were conducted to assess intestinal barrier function and elucidate underlying mechanisms, including histological analysis, immunofluorescence staining of tight junction proteins, 16S rDNA sequencing for gut microbiota profiling, transcriptomic analysis for gene expression patterns, and Western blot validation of key proteins. Furthermore, a multi-tiered experimental strategy was employed, integrating molecular modeling, machine learning algorithms, graph neural network (GNN) approaches and in vitro experiments using Caco-2 cell monolayers, to systematically validate the sGC-cGMP-PKG signaling pathway and identify bioactive compounds responsible for SLBZ's therapeutic effects.

SLBZ treatment markedly alleviated UC symptoms in mice and restored intestinal barrier function through dual mechanisms: upregulation of tight junction proteins (ZO-1/Occludin) and modulation of gut microbiota composition. Transcriptomic analysis pinpointed the cGMP-PKG signaling pathway as a central therapeutic target. Through an integrated approach combining molecular docking, machine learning (random forest algorithm), and deep neural network analysis, we identified soluble guanylate cyclase (sGC) as the primary molecular target, with Choerospondin emerging as a key bioactive component. Mechanistic investigations demonstrated that SLBZ robustly activated the sGC-cGMP-PKG axis both in vivo (colon tissues) and in vitro (Caco-2 cells), culminating in significant suppression of intestinal epithelial apoptosis.

SLBZ alleviates UC by activating the sGC-cGMP-PKG pathway to restore intestinal barrier function through tight junction upregulation and microbiota modulation. Our study both validates SLBZ's traditional use and identifies this pathway as a novel therapeutic target for UC.

Enantiomerically pure iron(II/III) lactates Λ-Fe^II(S-Hlact)₂(H₂O)₂ (1), Na[Λ-Fe^III(S-Hlact)₂(S-lact)]·3.5H₂O (2a) and Na[Δ-Fe^III(R-Hlact)₂(R-lact)]·3.5H₂O (2b), along with iron(II/III) citrates (H₂pz)₂[Fe^III₂(cit)₂(H₂O)₂]·2H₂O (3) and [Fe^II(Hpz)₄]_n[Fe^III₂(cit)₂(Hpz)₂]_n·2n(Hpz)·0.25nH₂O (4) (H₂lact = lactic acid, H₄cit = citric acid, Hpz = pyrazole) have been obtained. In 1 and 2, lactates chelate with iron bidentately through α-hydroxy/α-alkoxy and α-carboxy groups, respectively, forming stable five-membered chelated rings. Strong intermolecular hydrogen bonds have been found between α-hydroxy and α-alkoxy groups, with strong electron delocalization. For 3, citrate chelates one of the iron centers in a tridentate mode via its α-alkoxy, α-carboxy, and β-carboxy groups, leaving protonated pyrazole free. Further substitution of the coordinated water molecule in 3 results in the formation of mixed-valent pyrazole iron(II/III) citrate 4. The iron lactates and citrates show resemblance to the local environment of the active site of homocitrate and imidazole-coordinated FeFe-cofactor in Fe-only nitrogenase. The biological relevance has been discussed in details.