Search Results (5)

Our research explores the interplay between Aggregatibacter actinomycetemcomitans (Aa) cytolethal distending toxin (Cdt) and the host’s inflammatory response in molar/incisor pattern periodontitis (MIPP). Cdt disrupts phosphatidylinositol-3,4,5-triphosphate (PIP3) signaling, influencing cytokine expression through canonical and non-canonical inflammasome activation as well as nuclear factor-κB (NF-κB) activation, leading to inflammation in MIPP. THP-1 differentiated macrophages (TDMs) exposed to Cdt exhibited an upregulation of pro-inflammatory genes and subsequent cytokine release. We analyzed the ability of a small molecule therapeutic, LGM2605, known for its anti-inflammatory properties, to reduce pro-inflammatory gene expression and cytokine release in Cdt-exposed and Aa-inoculated TDMs. LGM2605’s mechanism of action involves inhibiting NF-κB while activating the Nrf2–transcription factor and antioxidants. Herein, we show that this small molecule therapeutic mitigates Cdt-induced pro-inflammatory cytokine expression and secretion. Our study also further defines Cdt’s impact on osteoclast differentiation and maturation in MIPP. Cdt promotes increased TRAP+ cells, indicating heightened osteoclast differentiation, specific to Cdt’s phosphatase activity. Cathepsin K levels rise during this process, reflecting changes in TRAP distribution between control and Cdt-treated cells. Exploring LGM2605’s effect on Cdt-induced osteoclast differentiation and maturation, we found TRAP+ cells significantly reduced with LGM2605 treatment compared to Cdt alone. Upon LGM2605 treatment, immunocytochemistry revealed a decreased TRAP intensity and number of multinucleated cells. Moreover, immunoblotting showed reduced TRAP and cathepsin K levels, suggesting LGM2605’s potential to curb osteoclast differentiation and maturation by modulating inflammatory cytokines, possibly involving Nrf2 activation. In summary, our research reveals the intricate connections between Cdt, pro-inflammatory cytokines, and osteoclast differentiation, offering novel therapeutic possibilities for managing these conditions. Full article

This study demonstrated the anticancer efficacy of chalcones with indole moiety (MIPP, MOMIPP) in fibrosarcoma cells for the first time. The results showed that MIPP and MOMIPP reduced the viability of HT-1080 cells in a concentration-dependent manner. MOMIPP was more active than MIPP in HT-1080 cells, showing lower IC₅₀ values (3.67 vs. 29.90 μM). Both compounds at a concentration of 1 μM induced apoptosis in HT-1080 cells, causing death strictly related to caspase activation, as cell viability was restored when the caspase inhibitor Z-VAD was added. Reactive oxygen species production was approximately 3-fold higher than in control cells, and cotreatment with the inhibitor of mitochondrial ATPase oligomycin diminished this effect. Such effects were also reflected in mitochondrial dysfunction, including decreased membrane potential. Interestingly, the compounds that were studied caused massive vacuolization in HT-1080 cells. Immunocytochemical staining and TEM analysis showed that HT-1080 cells exhibited increased expression of the LC3-II protein and the presence of autophagosomes with a double membrane, respectively. Both compounds induced apoptosis, highlighting a promising link between autophagy and apoptosis. This connection could be a new target for therapeutic strategies to overcome chemoresistance, which is a significant cause of treatment failure and tumour recurrence in fibrosarcoma following traditional chemotherapy. Full article

Molar–incisor pattern periodontitis (MIPP) is a severe form of periodontal disease characterized by rapid attachment loss and bone destruction affecting the molars and incisors. Formerly referred to as aggressive periodontitis, the terminology for this condition was revised after the 2017 workshop on the classification of periodontal and peri-implant diseases and conditions. Despite the modification in nomenclature, the treatment strategies for MIPP remain a critical area of investigation. The core principles of MIPP treatment involve controlling local and systemic risk factors, managing inflammation, and arresting disease progression. Traditional non-surgical periodontal therapy, including scaling and root planing, is commonly employed as an initial step together with the prescription of antibiotics. Surgical intervention may be necessary to address the severe attachment loss. Surgical techniques like resective and regenerative procedures can aid in achieving periodontal health and improving esthetic outcomes. This review article aims to provide an overview of the current understanding and advancements in the treatment modalities of MIPP. Through an extensive analysis of the existing literature, we discuss various modern therapeutic approaches that have been explored for managing this challenging periodontal condition. Full article

In the unmanned aerial vehicle (UAV) assisted non-orthogonal multiple access (NOMA) networks, the practical hardware impairments (HIs) and resource allocation is still a challenging problem. Most existing research on resource allocation algorithms for UAV communication is considered with the ideal hardware condition. However, the impact of HIs on system performance cannot be ignored, especially in the case of high bit rates. Considering the HIs, most studies are from the perspective of performance analysis. The resource allocation of UAV relay-assisted NOMA systems is investigated in this paper with HIs. We aim to maximize the sum rate by jointly optimizing the deployment of UAV and transmit power. To address this problem, we first transformed the mixed integer programming problem (MIPP) into a standard convex optimization problem based on successive convex approximation (SCA) technology. Then, we introduced the Lagrangian dual transformation and quadratic transform methods to solve the power allocation problem. Finally, we propose an effective iterative algorithm to achieve an approximate optimal solution. Numerical results demonstrate that the proposed algorithm achieved better performance in terms of the sum rate compared with other benchmark schemes. Full article

Human A₃ adenosine receptor hA₃AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A_2A adenosine receptor (hA_2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A_2A activity and instead conferred hA₃AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA₃AR partial agonist, with an E_max of 30% and EC₅₀ of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA₃AR partial agonists for the treatment of gastrointestinal cancers. Full article