3-methyl-1H-indol-1-yl dimethylcarbamodithioate attenuates periodontitis through targeting MAPK signaling pathway-regulated mitochondrial function.

Periodontitis, the second most common oral disease, is primarily initiated by inflammatory responses and osteoclast differentiation, in which the MAPK signaling pathway and mitochondrial function play important roles. 3-methyl-1H-indol-1-yl dimethylcarbamodithioate (3o), a hybrid of indole and dithiocarbamate, was first synthesized by our group. It has shown anti-inflammatory activity against lipopolysaccharide-induced acute lung injury. However, it is not known if 3o can exert effects in periodontitis. In vitro study: LPS-induced macrophage inflammation initiation and a receptor activator of nuclear factor κB ligand-stimulated osteoclast differentiation model were established. Cell viability, inflammatory cytokines, osteoclast differentiation, the MAPK signaling pathway, and mitochondrial function before and after treatment with 3o were investigated. In vivo study: Alveolar bone resorption, inflammatory cytokine expression, osteoclast differentiation, and the underlying mechanisms were assessed in mice with periodontitis. Inflammatory cytokine expression and osteoclast differentiation appeared downregulated after 3o treatment. 3o inhibited the MAPK signaling pathway and restored mitochondrial function, including mitochondrial reactive oxygen species, mitochondrial membrane potential, and ATP production. Meanwhile, 3o reduced inflammation activation and bone resorption in mice with periodontitis, reflected by the decreased expression of inflammatory cytokines and osteoclasts, implying that 3o inhibited the MAPK signaling pathway and the mitochondrial oxidative DNA damage marker 8-OHdG. These results highlight the protective role of 3o in periodontitis in mice and reveal an important strategy for preventing periodontitis.

Multi-level characteristics recognition of cancer core therapeutic targets and drug screening for a broader patient population.

Introduction: Target therapy for cancer cell mutation has brought attention to several challenges in clinical applications, including limited therapeutic targets, less patient benefits, and susceptibility to acquired due to their clear biological mechanisms and high specificity in targeting cancers with specific mutations. However, the identification of truly lethal synthetic lethal therapeutic targets for cancer cells remains uncommon, primarily due to compensatory mechanisms. Methods: In our pursuit of core therapeutic targets (CTTs) that exhibit extensive synthetic lethality in cancer and the corresponding potential drugs, we have developed a machine-learning model that utilizes multiple levels and dimensions of cancer characterization. This is achieved through the consideration of the transcriptional and post-transcriptional regulation of cancer-specific genes and the construction of a model that integrates statistics and machine learning. The model incorporates statistics such as Wilcoxon and Pearson, as well as random forest. Through WGCNA and network analysis, we identify hub genes in the SL network that serve as CTTs. Additionally, we establish regulatory networks for non-coding RNA (ncRNA) and drug-target interactions. Results: Our model has uncovered 7277 potential SL interactions, while WGCNA has identified 13 gene modules. Through network analysis, we have identified 30 CTTs with the highest degree in these modules. Based on these CTTs, we have constructed networks for ncRNA regulation and drug targets. Furthermore, by applying the same process to lung cancer and renal cell carcinoma, we have identified corresponding CTTs and potential therapeutic drugs. We have also analyzed common therapeutic targets among all three cancers. Discussion: The results of our study have broad applicability across various dimensions and histological data, as our model identifies potential therapeutic targets by learning multidimensional complex features from known synthetic lethal gene pairs. The incorporation of statistical screening and network analysis further enhances the confidence in these potential targets. Our approach provides novel theoretical insights and methodological support for the identification of CTTs and drugs in diverse types of cancer.

Interactive effect of 24-epibrassinolide and silicon on the alleviation of cadmium toxicity in rice (Oryza sativa L.) plants.

Cadmium (Cd) pollution is a serious threat to food safety and human health. Minimization of Cd uptake and enhancing Cd tolerance in plants are vital to improve crop yield and reduce hazardous effects to humans. In this study, we investigate the effect of a synergistic system with phytohormone (24-Epibrassinolide, EBL) and silicon (Si) on Cd toxicity and accumulation of rice plants. The results revealed that Si, EBL and their combination rescued Cd-induced growth inhibition, as evidenced by the increased dry weight of root and shoot. The chlorophyll content and photosynthetic performance were improved. The activity of antioxidant enzymes (SOD, POD and CAT) was increased and oxidative stress was alleviated. More importantly, Cd content in root was decreased by 20.25%, 17.72% and 27.84%, while Cd content in shoot decreased by 21.17%, 16.47% and 25.88%, respectively. Moreover, Si, EBL and Si + EBL treatment enriched cell wall-bound Cd and reduced Cd toxicity to functional organelles. Meanwhile, the residual form of Cd was enriched and the highly toxic forms of Cd (inorganic and water-soluble Cd) were decreased. The joint application showed better effects than applying Si and EBL alone. Collectively, this study provides an effective way for Cd toxicity mitigation in rice plants.

Akt-GSK3ß-mPTP pathway regulates the mitochondrial dysfunction contributing to odontoblasts apoptosis induced by glucose oxidative stress.

Diabetes Mellitus can cause dental pulp cells apoptosis by oxidative stress, and affect the integrity and function of dental pulp tissue. Mitochondria are the main attack targets of oxidative stress and have a critical role in apoptosis. However, whether mitochondria are involved in dental pulp damage caused by diabetes mellitus remains unclear. This study aimed to investigate the role of mitochondria in the apoptosis of odontoblast-like cell line (mDPC6T) induced by glucose oxidative stress, and to explore its possible mechanism. We established an oxidative stress model in vitro using glucose oxidase/glucose to simulate the pathological state under diabetic conditions. We found that the opening of mitochondrial permeability transition pore (mPTP) contributed to the apoptosis of mDPC6T treated with glucose oxidase, as evidenced by enhanced mitochondrial reactive oxygen species (mtROS) and intracellular Ca2+ disorder, significantly reduced mitochondrial membrane potential (MMP) and ATP production. Antioxidant N-acetylcysteine (NAC) or Cyclosporine A (mPTP inhibitor) blocked the mPTP opening, which significantly attenuated mitochondrial dysfunction and apoptosis induced by glucose oxidative stress. In addition, we found that glucose oxidative stress stimulated mPTP opening may through inhibition of Akt-GSK3ß pathway. This study provides a new insight into the mitochondrial mechanism underlying diabetes-associated odontoblast-like cell apoptosis, laying a foundation for the prevention and treatment of diabetes-associated pulp injury.

Hydroxytyrosol prevents periodontitis-induced bone loss by regulating mitochondrial function and mitogen-activated protein kinase signaling of bone cells.

Reactive oxygen species (ROS) overproduction promotes the alveolar bone loss during the development of periodontitis. Mitochondria are the principal source of ROS. Hydroxytyrosol (HT), a natural phenolic compound present in olive oil, is well known for its antioxidant and mitochondrial-protective prosperities. Nonetheless, the impact of HT on periodontitis and its related mechanisms underlying bone cell behavior remains unknown. Osteoclasts differentiated from RAW264.7 model and oxidative stress (OS) induced pre-osteoblast MC3T3-E1 cell injury model were treated with and without HT. Cell viability, apoptosis, differentiation, mitochondrial function along with mitogen-activated protein kinase (MAPK) signaling pathway were investigated. Meanwhile, the effect and related mechanisms of HT on bone loss in mice with periodontitis were also detected. HT inhibited osteoclast differentiation and prevented OS induced pre-osteoblast cells injury via regulating mitochondrial function as well as ERK and JNK signaling pathways. Moreover, HT attenuated the alveolar bone loss, increased bone forming activity, inhibited the osteoclasts differentiation and decreased the level of OS in mice with periodontitis. Our findings, for the first time, revealed a novel function of HT in bone remodeling of periodontitis, and highlighted its therapeutical potential for the prevention/treatment of periodontitis.

Notoginsenoside R1 alleviates TEGDMA-induced mitochondrial apoptosis in preodontoblasts through activation of Akt/Nrf2 pathway-dependent mitophagy.

Incomplete polymerization or biodegradation of dental resin materials results in the release of resin monomers such as triethylene glycol dimethacrylate (TEGDMA), causing severe injury of dental pulp cells. To date, there has been no efficient treatment option for this complication, in part due to the lack of understanding of the mechanism underlying these phenomena. Here, for the first time, we found that notoginsenoside R1 (NR1), a bioactive ingredient extracted from Panax notoginseng, exerted an obvious protective effect on TEGDMA-induced mitochondrial apoptosis in the preodontoblast mDPC6T cell line. In terms of the mechanism of action, NR1 enhanced the level of phosphorylated Akt (protein kinase B), resulting in the activation of a transcriptional factor, nuclear factor erythroid 2-related factor 2 (Nrf2), and eventually upregulating cellular ability to resist TEGDMA-related toxicity. Inhibiting the Akt/Nrf2 pathway by pharmaceutical inhibitors significantly decreased NR1-mediated cellular antioxidant properties and aggravated mitochondrial oxidative damage in TEGDMA-treated cells. Interestingly, NR1 also promoted mitophagy, which was identified as the potential downstream of the Akt/Nrf2 pathway. Blocking the Akt/Nrf2 pathway inhibited mitophagy and abolished the protection of NR1 on cells exposed to TEGDMA. In conclusion, these findings reveal that the activation of Akt/Nrf2 pathway-mediated mitophagy by NR1 might be a promising approach for preventing resin monomer-induced dental pulp injury.

JNK-mediated blockage of autophagic flux exacerbates the triethylene glycol dimethacrylate-induced mitochondrial oxidative damage and apoptosis in preodontoblast.

Mitochondrial dependent oxidative stress (OS) and subsequent cell death are considered as the major cytotoxicity caused by Triethylene glycol dimethacrylate (TEGDMA), a commonly monomer of many resin-based dental composites. Under OS microenvironment, autophagy serves as a cell homeostatic mechanism and maintains redox balance through degradation or turnover of cellular components in order to promote cell survival. However, whether autophagy is involved in the mitochondrial oxidative damage and apoptosis induced by TEGDMA, and the cellular signaling pathways underlying this process remain unclear. In the present study, we demonstrated that TEGDMA induced mouse preodontoblast cell line (mDPC6T) dysfunctional mitochondrial oxidative response. In further exploring the underlying mechanisms, we found that TEGDMA impaired autophagic flux, as evidenced by increased LC3-II expression and hindered p62 degradation, thereby causing both mitochondrial oxidative damage and cell apoptosis. These results were further verified by treatment with chloroquine (autophagy inhibitor) and rapamycin (autophagy promotor). More importantly, we found that the JNK/MAPK pathway was the key upstream regulator of above injury process. Collectively, our finding firstly demonstrated that TEGDMA induced JNK-dependent autophagy, thereby promoting mitochondrial dysfunction-associated oxidative damage and apoptosis in preodontoblast.