Search

In traditional Chinese medicine, propolis has been used for treating oral diseases for centuries, widely. Flavonoid extract is the main active ingredient in propolis, which has attracted extensive attention in recent years. The objective and novelty of the current study aims to identify the mechanism of total flavonoid extract of propolis (TFP) for the treatment of periodontitis, and evaluate the therapeutic effect of TFP-loaded liquid crystal hydrogel (TFP-LLC) in rats with periodontitis. In this study, we used lipopolysaccharide-stimulated periodontal ligament stem cells (PDLSCs) to construct in vitro inflammation model, and investigated the anti-inflammatory effect of TFP by expression levels of inflammatory factors. Osteogenic differentiation was assessed using alkaline phosphatase activity and alizarin red staining. Meanwhile, the expression of toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor-kappa B (NF- κ B), receptor activator of NF- κ B (RANK) etc, were quantitated to investigate the therapeutic mechanism of TFP. Finally, we constructed TFP-LLC using a self-emulsification method and administered it to rats with periodontitis via periodontal pocket injection to evaluate the therapeutic effects. The therapeutic index, microcomputed tomography (Micro-CT), H&E staining, TRAP staining, and Masson staining were used for this evaluation. TFP reduced the expression of TLR4, MyD88, NF- κ B and inflammatory factor in lipopolysaccharide-stimulated PDLSCs. Meanwhile, TFP simultaneously regulating alkaline phosphatase, RANK, runt-associated transcription factor-2 and matrix metalloproteinase production to accelerate osteogenic differentiation and collagen secretion. In addition, TFP-LLC can stably anchor to the periodontal lesion site and sustainably release TFP. After four weeks of treatment with TFP-LLC, we observed a decrease in the levels of NF- κ B and interleukin-1 β (IL-1β) in the periodontal tissues of rats, as well as a significant reduction in inflammation in HE staining. Similarly, Micro CT results showed that TFP-LLC could significantly inhibit alveolar bone resorption, increase bone mineral density (BMD) and reduce trabecular bone space (Tb.Sp) in rats with periodontitis. Collectively, we have firstly verified the therapeutic effects and mechanisms of TFP in PDLSCs for periodontitis treatment. Our results indicate that TFP perform anti-inflammatory and tissue repair activities through TLR4/MyD88/NF-κB and RANK/NF- κ B pathways in PDLSCs. Meanwhile, for the first time, we employed LLC delivery system to load TFP for periodontitis treatment. The results showed that TFP-LLC could be effectively retained in the periodontal pocket and exerted a crucial role in inflammation resolution and periodontal tissue regeneration. Scheme 1. Schematic diagram of TFP-LLC alleviating periodontitis via PDLSCs-dependent anti-inflammatory and periodontium regeneration mechanism. TFP–LLC was in situ injected into the periodontal pocket to ensure the sustained release of the active TFP ingredients at the periodontal lesion. TFP–LLC suppresses the expression of inflammatory factors and osteoclastogenesis by interfering with TLR4/MyD88/NF-κB and RANK/NF-κB signaling. In addition, TFP–LLC promotes osteogenic differentiation and collagen regeneration in PDLSCs, as demonstrated by the upregulation of ALP and RUNX2 and downregulation of MMP. The TFP–LLC-induced periodontal homeostasis alleviates acute periodontal inflammation and assists in the long-term tissue regeneration of the gingiva, cementum, periodontal ligament, and alveolar bone, thereby demonstrating comprehensive treatment efficacy in periodontitis. [Display omitted] • We demonstrated that TFP exerts an anti-inflammatory pathway through TLR4/MyD88/NF-κB pathway in PDLSCs. • We proved TFP boosting periodontium regeneration via RANK/NF- κ B pathway in PDLSCs. • We prepared lyotropic liquid crystals containing total flavonoid extract of propolis (TFP-LLC). • TFP-LLC was stably anchored to the periodontal lesion site to form a drug reservoir. • TFP-LLC demonstrated excellent periodontal protection in rats with periodontitis. [ABSTRACT FROM AUTHOR]

• NF exerts anti-endometritis effects via inhibiting NF-κB signaling pathway; • NF protects against LPS-induced endometritis by inhibiting ferroptosis; • NF protects against LPS-induced endometritis by modulating AMPKα/mTOR/HIF-1α signaling axis; Nuciferine (NF) is an alkaloid isolated from Nelumbo nucifera and has been reported to exhibit a wide range of pharmacological effects. However, whether NF treatment exhibits a protective effect in endometritis remains unclear. Here, the protective effects of NF on lipopolysaccharide (LPS)-induced endometritis in mice were investigated in our research. The results showed that NF significantly reversed the uterine histopathological changes, inflammatory factor levels and myeloperoxidase (MPO) activity caused by LPS. Furthermore, we found that NF administration improved the reproductive capacity of mice with endometritis. Mechanistically, the expression of MyD88/nuclear factor-kappa B (NF-κB) and MAPK-related proteins in uterine tissue were decreased by NF treatment. Moreover, we observed the occurrence of ferroptosis in the LPS-induced endometritis mouse model, which was noticeably inhibited by NF treatment. In addition, we showed that NF exhibited anti-endometritis activity by modulating AMPKα/mTOR/HIF1α signaling axis. Finally, the molecular mechanism of the NF anti-inflammatory effect was clarified in mouse endometrial epithelial cells (mEECs). NF inhibited the releases of pro-inflammatory factors in LPS-induced mEECs via inhibiting NF-κB signaling pathway. All these findings suggest that NF may ameliorate LPS-induced endometritis caused by LPS, the mechanism of action is related to the ferroptosis, MyD88/NF-κB, MAPK and AMPKα/mTOR/HIF1α signaling pathway. [ABSTRACT FROM AUTHOR]

To investigate the potential link between aberrant mitochondrial energy metabolism mediated by the AMPK/SIRT1 pathway and the etiology of anxiety disorders. The anxiety rat model was established by uncertain empty water bottle（UEWB）stress. Rats were submitted behavioral tests on the seventh, fourteenth, and twenty-first days and had the prefrontal cortex and amygdala removed for biochemical tests. The morphological alterations of the mitochondria in the medial prefrontal cortex and amygdala were examined by using a transmission electron microscope. Expression levels of AMPK, SIRT1, PGC-1, NRF-1 and NRF-2 were tested by western-blot analysis. ATP, respiratory chain complex and caspase enzyme expressions were tested by neurochemical and biochemical assays. Rats showed anxiety-like behavior after being exposed to the uncertain empty water bottle (UEWB) stress model. In model rats, mitochondrial structure is damaged, mitochondrial energy metabolism is decreased, and the expression of proteins associated with AMPK/SIRT1 pathway is significantly reduced in the brain. The level of mitochondrial energy metabolism correlates with anxiety-like behavior. The main mechanism of anxiety disorder is a disturbance of mitochondrial energy metabolism, which might be related to AMPK/SIRT1 pathway. • Uncertain empty water bottle stress model induces anxiety-like behavior in animals. • Mitochondrial structures are disrupted in anxious animals. • Disruption of mitochondrial energy metabolic function is associated with anxiety-like behavior. • Inhibition of AMPK/SIRT1 pathway may be a regulatory mechanism for decreased mitochondrial function. [ABSTRACT FROM AUTHOR]

IFNLR1 has been recently identified to be related to autosomal dominant nonsyndromic sensorineural hearing loss (ADNSHL). It is reported to be expressed in the inner ear of mice and the lateral line of zebrafish. However, it remains unclear how defects in this gene lead to hearing loss. To elucidate the global gene expression changes in zebrafish when the expression of ifnlr1 is downregulated. Transcriptome analysis was performed on ifnlr1 morpholino knockdown zebrafish and the control zebrafish using RNA-seq technology. The results show that 262 differentially expressed genes (DEGs) were up-regulated while 146 DEGs were down-regulated in the E4I4–Mo zebrafish larvae compared to the control-Mo. Six pathways were significantly enriched, including steroid biosynthesis pathway, adipocytokine signaling pathway, cytokine-cytokine receptor interaction pathway, p53 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and terpenoid backbone biosynthesis pathway. Among them, three pathways (steroid biosynthesis pathway, cytokine-cytokine receptor interaction pathway and p53 signaling pathway) are immune-associated. The transcriptome analysis results contribute to the groundwork for future research on the pathogenesis of IFNLR1 -associated hearing loss. [ABSTRACT FROM AUTHOR]