RESUMEN

BACKGROUND: Atopic dermatitis is a common chronic inflammatory skin disease characterized by relapsing eczema and intense itch. DGT is a novel synthetic heterocyclic diterpenoid derived from plants. Its therapeutic potential and mechanism(s) of action are poorly understood. OBJECTIVES: We investigated the potent therapeutic effect of DGT on atopic dermatitis, exploring the underlying mechanisms and determining whether DGT is a safe and well-tolerated topical treatment. METHODS: We observed anti-inflammatory effects of DGT on tumor necrosis factor-α/interferon-γ-treated human keratinocytes, and anti-allergic effects on immunoglobulin E-sensitized bone marrow-derived mast cells. In vivo, DGT was topically applied to two experimental mouse models of atopic dermatitis: oxazolone-induced sensitization and topically applied calcipotriol. Then the therapeutic effects of DGT were evaluated physiologically and morphologically. Moreover, we performed nonclinical toxicology and safety pharmacology research, including general toxicity, pharmacokinetics, and safety pharmacology on the cardiovascular, respiratory, and central nervous systems. RESULTS: In keratinocytes, DGT reduced the expression of inflammatory factors, promoting the expression of barrier functional proteins and tight junctions and maintaining the steady state of barrier function. DGT also inhibited the activation and degranulation of mast cells induced by immunoglobulin E. Moreover, we found that interleukin-4 receptor-α was the possible target of DGT. Meanwhile, DGT had therapeutic effects on oxazolone/calcipotriol-treated mice. Notably, our pharmacology results demonstrated that DGT was safe and nontoxic in our studies. CONCLUSION: DGT's potent anti-inflammatory effects and good safety profile suggest that it is a potential candidate for the treatment of atopic dermatitis.

RESUMEN

Ulcerative colitis, a chronic inflammatory condition affecting the rectum and colon to varying degrees, is linked to a dysregulated immune response and the microbiota. Sodium (aS,9R)-3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) emerges as a novel diarylheptane compound aimed at treating inflammatory bowel diseases. However, the mechanisms by which SDH modulates these conditions remain largely unknown. In this study, we assessed SDH's impact on the clinical progression of dextran sodium sulfate (DSS)-induced ulcerative colitis. Our results demonstrated that SDH significantly mitigated the symptoms of DSS-induced colitis, reflected in reduced disease activity index scores, alleviation of weight loss, shortening of the colorectum, and reduction in spleen swelling. Notably, SDH decreased the proportion of Th1/Th2/Th17 cells and normalized inflammatory cytokine levels in the colon. Furthermore, SDH treatment modified the gut microbial composition in mice with colitis, notably decreasing Bacteroidetes and Proteobacteria populations while substantially increasing Firmicutes, Actinobacteria, and Patescibacteria. In conclusion, our findings suggest that SDH may protect the colon from DSS-induced colitis through the regulation of Th1/Th2/Th17 cells and gut microbiota, offering novel insights into SDH's therapeutic potential.

Asunto(s)

Colitis Ulcerosa , Sulfato de Dextran , Diarilheptanoides , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Diarilheptanoides/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Colon/efectos de los fármacos , Colon/inmunología , Colon/patología , Colon/microbiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/inmunología , Colitis/microbiología , Masculino , Células TH1/inmunología , Células TH1/efectos de los fármacos , Células Th17/inmunología , Células Th17/efectos de los fármacos , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Células Th2/inmunología , Células Th2/efectos de los fármacos , Humanos

RESUMEN

To date, colorectal cancer (CRC) still has limited therapeutic efficacy and poor prognosis and there is an urgent need for novel targets to improve the outcome of CRC patients. The highly conserved ubiquitination modification mediated by E3 ubiquitin ligases is an important mechanism to regulate the expression and function of tumor promoters or suppressors in CRC. In this review, we provide an overview of E3 ligases in modulating various biological processes in CRC, including proliferation, migration, stemness, metabolism, cell death, differentiation and immune response of CRC cells, emphasizing the pluripotency of E3 ubiquitin ligases. We further focus on the role of E3 ligases in regulating vital cellular signal pathways in CRC, such as Wnt/ß-catenin pathway and NF-κB pathway. Additionally, considering the potential of E3 ligases as novel targets in the treatment of CRC, we discuss what aspects of E3 ligases can be utilized and exploited for efficient therapeutic strategies.

RESUMEN

BACKGROUND AND PURPOSE: Psoriasis is a chronic immune-mediated inflammatory skin disease that easily recurs and is difficult to cure. DGT is a novel synthetic heterocyclic diterpenoid, whose structure has not been previously reported. We have investigated the action of DGT against psoriasis, specifically the hyperproliferation of epidermal keratinocytes, angiogenesis and pathogenic inflammatory responses. EXPERIMENTAL APPROACH: We investigated its pharmacokinetics in skin after topical administration. We characterized its pharmacological actions in vitro and in vivo using cell proliferation assay, cell apoptosis assay, diethylstilbestrol-induced mouse vaginal epithelial cell mitosis model, tube formation assay, cell migration assay, chick embryonic chorioallantoic membrane (CAM) assay, histological, flow cytometric analysis and imiquimod (IMQ)-induced psoriasis-like model. KEY RESULTS: DGT was found to be mainly distributed in the epidermis and dermis, which indicated that DGT was suitable as a topical treatment. DGT inhibited cell proliferation and induced apoptotic cell death of keratinocytes in vitro and in vivo. Moreover, DGT inhibited endothelial cell proliferation, tube formation and migration of in vitro angiogenesis, as well as in vivo CAM angiogenesis. In an IMQ-induced psoriasis-like skin inflammation murine model, topical application of DGT ameliorated keratinocyte proliferation and inflammatory response, especially in IL-17-related psoriasiform dermatitis. Furthermore, our results demonstrated that DGT prevented these pathological processes of psoriasis through suppression of STAT3 phosphorylation. CONCLUSION AND IMPLICATIONS: DGT has great potential as a novel therapeutic agent for the treatment of psoriatic skin disease.

Asunto(s)

Diterpenos , Psoriasis , Animales , Modelos Animales de Enfermedad , Diterpenos/farmacología , Femenino , Imiquimod/metabolismo , Imiquimod/toxicidad , Queratinocitos , Ratones , Ratones Endogámicos BALB C , Fosforilación , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Piel/metabolismo

RESUMEN

In the title compound, C(15)H(13)FN(2)O(3), the aromatic rings are aligned at an angle of 10.15 (3)°. The mol-ecules are packed with π-π stacking inter-actions [mean inter-planar distances of 3.339 (2) and 3.357 (3) Å] and the crystal structure is stabilized by inter-molecular N-H⋯O and O-H⋯O hydrogen bonds. An intramolecular N-H⋯O interaction also occurs.

RESUMEN

In the title Schiff base, C(15)H(15)NO, the benzene rings form a dihedral angle of 74.91 (1)°. There is a strong intra-molecular O-H⋯N hydrogen bond.

RESUMEN

In the title compound, C(18)H(14)N(2)O(3), the dihedral angle between the planes of the naphthalene and phenyl ring systems is 2.64 (2)°. Mol-ecules are engaged in π-π stacking (mean interplanar distance = 3.339 between naphthalene rings and 3.357 Šbetween benzene rings )and hydrogen-bonding inter-actions.

RESUMEN

The asymmetric unit of the title compound, 2C(11)H(14)N(2)O(3)·C(16)H(16)N(2)O(4), contains one mol-ecule of 2-hydr-oxy-4-methyl-N-propanoylbenzohydrazide and one-half of a mol-ecule of 2-hydr-oxy-N-(2-hydr-oxy-4-methyl-benzo-yl)-6-methyl-benzohydrazide. The latter is located on a centre of inversion. Intra-molecular N-H⋯O inter-actions stabilize the conformations of both mol-ecules. The crystal structure is stabilized by inter-molecular N-H⋯O and O-H⋯O hydrogen bonds.

RESUMEN

In the title Schiff base, C(22)H(20)N(2)O(2), the benzene ring forms dihedral angles of 53.92 (1) and 3.62 (1)° with the two salicylaldimine groups. There are two strong O-H⋯N intra-molecular hydrogen bonds. The crystal packing is stabilized by weak inter-molecular C-H⋯O hydrogen bonds and π-π stacking inter-actions (average distance 3.39 Å).