Amplification of oxidative damage using near-infrared II-mediated photothermal/thermocatalytic effects for periodontitis treatment.

Periodontitis is a biofilm-related disease characterized by damage to the periodontal tissue and the development of systemic diseases. However, treatment of periodontitis remains unsatisfactory, especially with deep-tissue infections. This study describes rationally designed multifunctional photothermocatalytic agents for near-infrared-II light-mediated synergistic antibiofilm treatment, through modification of Lu-Bi2Te3 with Fe3O4 and poly(ethylene glycol)-b-poly(l-arginine) (PEG-b-PArg). Notably, 1064-nm laser irradiation led to photothermal/thermocatalytic effects, resulting in the synergistic generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and consequent damage to the biofilm. This treatment was based on the thermoelectric and photothermal conversion properties of Lu-Bi2Te3, the peroxidase-like catalytic capacity of Fe3O4, and the guanidinium polymer, PEG-b-PArg. Oxidative damage to biofilm was further enhanced by H2O2, resulting in the effective elimination of biofilm both in vitro and in vivo. These findings suggest that this synergistic therapeutic strategy is effective for the clinical treatment of periodontitis. STATEMENT OF SIGNIFICANCE: The current treatment for periodontitis involves time-consuming and labor-intensive clinical scaling of the teeth. The present study is the first to assess the efficacy of a photothermal catalyst for periodontitis treatment. This used near-infrared-II light at 1064 nm to induce oxidative damage in the biofilm, resulting in its degradation. The synergistic photothermal/thermoelectric effect produced deep tissue penetration and was well tolerated, and can kill the biofilm formed by periodontitis pathogens up to 5 orders of magnitude, effectively treating the biofilm-induced periodontitis.

Apigenin inhibits macrophage pyroptosis through regulation of oxidative stress and the NF-κB pathway and ameliorates atherosclerosis.

Pyroptosis plays an important role in inflammatory diseases such as viral hepatitis and atherosclerosis. Apigenin exhibits various bioactivities, particularly anti-inflammation, but its effect on pyroptosis remains unclear. The aim of this study is to investigate the effect of apigenin on pyroptosis and explore its potential against inflammatory diseases. THP-1 macrophages treated by lipopolysaccharides/adenosine 5'-triphosphate were used as the in vitro pyroptosis model. Western blot was used to detect the expression of NLRP3 inflammasome components and key regulators. Immunofluorescence was used to observe ROS production and intracellular location of p65. The potential of apigenin against inflammatory diseases was evaluated using atherosclerotic mice. Plaque progression was observed by pathological staining. Immunofluorescence was used to observe the expression of NLRP3 inflammasome components in plaques. The results showed that apigenin inhibited NLRP3 inflammasome activation. Apigenin reduced ROS overproduction and inhibited p65 nuclear translocation. Additionally, apigenin decreased the expression of NLRP3 inflammasome components in the plaque. Plaque progression was inhibited by apigenin. In conclusion, apigenin exhibited a preventive effect on macrophage pyroptosis by reducing oxidative stress and inhibiting the NF-κB pathway. Apigenin may alleviate atherosclerosis at least partially by inhibiting macrophage pyroptosis. These findings suggest apigenin to be a promising therapeutic agent for inflammatory diseases.

Liraglutide Plus Dapagliflozin for High Uric Acid and Microalbuminuria in Diabetes Mellitus Complicated With Metabolic Syndrome.

Context: Diabetes mellitus (DM) represents an emerging epidemic, poses serious threats to human health, and can seriously compromise patients' quality of life (QoL). Currently, no cure exists for DM. Some studies have found that both liraglutide and dapagliflozin have great therapeutic potential in preventing and treating DM and its complications. Objective: The study aimed to examine the impact of liraglutide plus dapagliflozin on high uric acid (UA) and microalbuminuria (MAU) in patients with diabetes mellitus (DM) complicated with metabolic syndrome (MS). Design: The research team designed a randomized controlled trial. Setting: The study took place at the Second Affiliated Hospital of Nanjing Medical University in Nanjing, Jiangsu, China. Participants: Participants were 125 patients with DM complicated with MS who were treated in the outpatient clinic of the endocrinology department at the hospital between January 1, 2020 and December 31, 2021, with 68 in the intervention group and 57 in the control group. Intervention: The intervention and control groups both received 0.6 mg of liraglutide. The intervention group also received 5 mg of dapagliflozin once a day. The dosages were increased at one week after baseline based on the participant's condition. Outcome Measures: Therapeutic effects, glycolipid metabolism, inflammation, uric acid (UA), microalbuminuria (MAU), cardiac function, and quality of life (QoL) were compared between the two groups. Results: Postintervention, the clinical efficacy was significantly higher in the intervention group than in the control group. The intervention group had significantly lower glycolipid metabolism and inflammatory-factor levels than the control group UA and MAU had declined in both groups but were significantly lower in the intervention group. The left ventricular ejection fraction (LVEF) increased and the left ventricular end diastolic diameter (LVEDd) decreased in both groups, but the intervention group had significantly greater changes as compared with those in the control group. The intervention group was also superior to the control group in patients' QoL. Conclusions: Liraglutide plus dapagliflozin has highly therapeutic effect for patients with DM complicated with MS and can effectively reduce UA and MAU levels. The current research team will launch a more comprehensive analysis as soon as possible to obtain the most accurate results.

Preparation and Characterization of Fe3O4@MTX Magnetic Nanoparticles for Thermochemotherapy of Primary Central Nervous System Lymphoma in vitro and in vivo.

BACKGROUND: Primary central nervous system lymphomas (PCNSL) are extranodal malignant non-Hodgkin lymphomas (NHL) that arise exclusively in central nervous system (CNS). Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype. PURPOSE: To evaluate whether nano drug-loading system-mediated magnetic-targeted thermochemotherapy could produce a better therapeutic effect than single chemotherapy while reducing the use of chemotherapeutic drugs. METHODS: Six groups (control, Fe3O4, MTX, Fe3O4@MTX, Fe3O4 with hyperthermia and Fe3O4@MTX with hyperthermia) were set. Tumor cell apoptosis in each treatment group was detected by flow cytometry. Apoptosis-related gene expressions Caspase-3, Bax and Bcl-2 were detected by qPCR and Western blot; intracranial tumor model of PCNSL was established by intracranial injection of OCI-LY18 tumor cells into BALB/c-Nude mice. Magnetic resonance imaging (MRI) was used to monitor tumor progression and H&E staining was used to observe pathological changes of the tumor tissue. RESULTS: In vitro, compared with chemotherapy alone, apoptosis rate of Fe3O4@MTX mediated thermochemotherapy group was significantly increased, and expression of apoptosis-inducing gene Caspase-3 and Bax were significantly upregulated in OCI-LY18 cells, while expression of apoptosis-inhibiting Bcl-2 gene was significantly downregulated. In vivo, MRI showed successful generation of intracranial tumor, and tumor volume was significantly smaller in combined thermochemotherapy group than in single chemotherapy group. H&E staining result of tumor tissues in each group was consistent with MRI; tumor cells were significantly reduced in thermochemotherapy group. Expression of apoptosis-related gene Caspase-3 and Bax were significantly upregulated in tumor tissues, while expression of Bcl-2 gene was significantly downregulated. CONCLUSION: These results demonstrated in vivo and in vitro that the combined thermochemotherapy of Fe3O4@MTX MNPs was superior to the single MTX chemotherapy with less dosage, which may promote apoptosis of DLBCL cells through the mitochondrial apoptotic pathway and provided a new way for the treatment of PCNSL.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells.

BACKGROUND: Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. METHODS: The core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. RESULTS: The inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. CONCLUSION: Our studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future.

EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy.

The epidermal growth factor receptor (EGFR) pathway and Hippo signaling play an important role in the carcinogenesis of hepatocellular carcinoma (HCC). However, the crosstalk between these two pathways and its implications in targeted therapy remains unclear. We found that the activated EGFR signaling could bypass RhoA to promote the expression of YAP(Yes-associated protein), the core effector of the Hippo signaling, and its downstream target Cyr61. Further studies indicated that EGFR signaling mainly acted through the PI3K-PDK1 (Phosphoinositide 3-kinase-Phosphoinositide-dependent kinase-1) pathway to activate YAP, but not the AKT and MAPK pathways. While YAP knockdown hardly affected the EGFR signaling. In addition, EGF could promote the proliferation of HCC cells in a YAP-independent manner. Combined targeting of YAP and EGFR signaling by simvastatin and the EGFR signaling inhibitors, including the EGFR tyrosine kinase inhibitor (TKI) gefitinib, the RAF inhibitor sorafenib and the MEK inhibitor trametinib, presented strong synergistic cytotoxicities in HCC cells. Therefore, the EGFR-PI3K-PDK1 pathway could activate the YAP signaling, and the activated EGFR signaling could promote the HCC cell growth in a YAP-independent manner. Combined use of FDA-approved inhibitors to simultaneously target YAP and EGFR signaling presented several promising therapeutic approaches for HCC treatment.