Highly modified cephalotane-type diterpenoids from Cephalotaxus fortunei var. alpina and C. sinensis.

Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis, leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A-F (1-6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13-p-hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents.

Reversible SAHH inhibitor ameliorates MIA-induced osteoarthritis of rats through suppressing MEK/ERK pathway.

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.

DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway.

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.

Three-dimensional finite element analysis of maxillary incisor retraction with step-shaped vertical closing loop / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the displacement and stress distribution of upper incisors in three-dimensional (3D) space controlled by step-shaped vertical closing loop.</p><p><b>METHODS</b>The maxillary teeth and alveolar bone of a volunteer with normal occlusion were scanned with 3D spiral CT. Modeling and calculation were only carried out on right upper central incisor, lateral incisor and their alveolar bone in order to simplify the procedures. A 3D finite element model of archwire-brackets-upper incisors and periodontal tissues was developed using Ansys finite element package. Finally, a 3D finite element model of archwire-brackets-upper incisors and periodontal tissues was established based on mirror symmetry principle. The displacement of maxillary incisors and stress distribution in periodontal tissues were analyzed.</p><p><b>RESULTS</b>When step-shaped vertical closing loop was simply drew back 1 mm, the maximum displacement of upper central incisor in labial and lingual direction were 5.29 × 10(-2) and 0.71 × 10(-2) mm; 10.47 × 10(-3) and 10.20 × 10(-3) mm in gingival and occlusal direction, 10.26 × 10(-3) and 1.63 × 10(-3) mm in medial and distal direction; the maximum displacement of upper lateral incisor in labial and lingual direction were 3.31 × 10(-2) and 0.41 × 10(-2) mm, 10.52 × 10(-3) and 5.10 × 10(-3) mm in gingival and occlusal direction, 6.29 × 10(-3) and 4.64 × 10(-3) mm in medial and distal direction, the displacement trend of them were moving lingually and gingivally similar to bodily movement. The stress peach of upper central incisor, periodontal ligament and alveolar bone were 31.35, 2.52 and 4.64 MPa, the stress peach of upper lateral incisor, periodontal ligament and alveolar bone were 19.59, 1.28 and 4.12 Mpa, the stress distribution of them were similar and the periodontal ligament buffered the stress imposed on the tooth.</p>