Acacetin inhibited non-small-cell lung cancer (NSCLC) cell growth via upregulating miR-34a in vitro and in vivo.

Acacetin, one of the flavonoid compounds, is a natural product found in various plants, including Silver birch, and Damiana. Previous studies showed that acacetin has anti-cancer effects on many kinds of cancer cells, however, the role of and the mechanisms of actions of acacetin on non-small cell lung cancer (NSCLC) cells is still not fully understood. Herein, we found that, in vitro, acacetin inhibited the proliferation, invasion, and migration of NSCLC cells, A549 and H460, in a dose-dependent manner. Meanwhile, flow cytometry assay results showed that acacetin induced G2/M phase cell cycle arrest, and apoptosis of NSCLC cells. In vivo, acacetin suppressed tumor formation of A549-xenografted nude mice model with no obvious toxicities. Western blotting results showed that the protein levels of cell cycle-related proteins cyclin B1, cyclin D, and anti-apoptotic protein Bcl-2 had decreased, while the apoptosis-related protein Bak had increased both in NSCLC cells and in A549-xenografted tumor tissues. For investigating the molecular mechanism behind the biological effects of acacetin on NSCLC, we found that acacetin induced the expression levels of tumor suppressor p53 both in vitro and in vivo. MicroRNA, miR-34a, the direct target of p53, has been shown anti-NSCLC proliferation effects by suppressing the expression of its target gene programmed death ligand 1 (PD-L1). We found that acacetin upregulated the expression levels of miR-34a, and downregulated the expression levels of PD-L1 of NSCLC cells in vitro and of tumors in vivo. In vitro, knockdown p53 expression by siRNAs reversed the induction effects of acacetin on miR34a expression and abolished the inhibitory activity of acacetin on NSCLC cell proliferation. Furthermore, using agomir and antagomir to overexpress and suppress the expression miR-34a in NSCLC cells was also examined. We found that miR-34a agomir showed similar effects as acacetin on A549 cells, while miR-34a antagomir could partially or completely reverse acacetin's effects on A549 cells. In vivo, intratumor injection of miR-34a antagomir could drastically suppress the anti-tumor formation effects of acacetin in A549-xenografted nude mice. Overall, our results showed that acacetin inhibits cell proliferation and induces cell apoptosis of NSCLC cells by regulating miR-34a.

Liproxstatin-1 alleviates ferroptosis in sevoflurane anesthesia-induced cognitive deficits of aged mice: The role oxidative stress.

In this study, we aimed to validate the hypothesis that the interplay between sevoflurane, oxidative stress and ferroptosis is crucial for the pathogenesis of sevoflurane-induced cognitive impairment in aged individuals. The mice with sevoflurane-induced cognitive impairment were used to explore the effects of sevoflurane on oxidative stress, iron homeostasis, and cognitive function in aged mice. Iron content and oxidative stress markers were analyzed in hippocampal tissue homogenates using specific assays. Additionally, the levels of iron death-related markers (Fth1 and Gpx4) were assessed by real-time PCR and Western blotting. Morris Water Maze and novel object recognition (NOR) tests were conducted to evaluate cognitive function. Sevoflurane exposure in aged mice resulted in a significant increase in iron overloading in the hippocampus, followed by a subsequent stabilization. Oxidative stress levels were elevated in the hippocampal tissue of sevoflurane-exposed mice, and a significant correlation was observed between iron death and oxidative stress. Liproxstatin-1, a ferroptosis inhibitor, effectively ameliorated the decline in memory and learning abilities induced by sevoflurane anesthesia. Liproxstatin-1 treatment reduced iron overload and oxidative stress in the hippocampal tissue of aged mice. The expression of Fth1 and Gpx4, iron death-related markers, was downregulated following Liproxstatin-1 intervention. Our findings suggest that sevoflurane anesthesia disrupts iron homeostasis, leading to increased oxidative stress and cognitive impairment in aged mice. These results highlight the potential of targeting iron-mediated processes to mitigate sevoflurane-induced cognitive impairment in the aging population.

Potential role of mesenchymal stem cells in T cell aging.

Immunosenescence occurs with progressive age. T cell aging is manifested by immunodeficiency and inflammation. The main mechanisms are thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, loss of protein stability, reduction of T cell receptor (TCR) repertoire, naïve-memory T cell ratio imbalance, T cell senescence, and lack of effector plasticity. Mesenchymal stem cells (MSCs) are thought to hold great potential as anti-aging therapy. However, the role of MCSs in T cell aging remains elusive. This review makes a tentative summary of the potential role of MSCs in the protection against T cell aging. It might provide a new idea to intervene in the aging of the immune system.

The Role of Mesenchymal Stem Cells in Cancer Immunotherapy.

Mesenchymal stem cells (MSCs) are getting attention in the field of cancer immunotherapy. The main effects of MSCs on tumors are homing and regulation of inflammatory and immune responses. Indeed, cancer immunotherapy has become a promising treatment and MSCs play a potential role in regulating the efficacy of immunotherapy. In addition, MSCs are an ideal carrier for immunomodulatory protein transmission. As such MSCs combined with immunotherapy drugs could act synergistically against tumors, throwing a great impact on cancer therapy. And MSCs may have potential in the treatment of cytokine storm or cytokine release syndrome (CRS). It is assumed that MSCs can form chimeric antigen receptor MSCs (CAR-MSCs). Whether CAR-MSCs can provide a new idea of cancer immunotherapy is unknown. It is a prime time to review the latest progress of MSCs in cancer immunotherapy, in order to clarify to fully understand the role of MSCs in cancer therapy in clinical practice.

Porphyromonas gingivalis Outer Membrane Vesicles Promote Apoptosis via msRNA-Regulated DNA Methylation in Periodontitis.

The outer membrane vesicles (OMVs) produced by Porphyromonas gingivalis contain a variety of bioactive molecules that may be involved in the progression of periodontitis. However, the participation of P. gingivalis OMVs in the development of periodontitis has not been elucidated. Here, we isolated P. gingivalis OMVs and confirmed their participation in periodontitis both in vivo and in vitro. Microcomputed tomography (micro-CT) and histological analysis showed that under stimulation with P. gingivalis OMVs, the alveolar bone of rats was significantly resorbed in vivo. We found that P. gingivalis OMVs were taken up by human periodontal ligament cells ([hPDLCs]) in vitro, which subsequently resulted in apoptosis and inflammatory cytokine release, which was accomplished by the microRNA-size small RNA (msRNA) sRNA45033 in the P. gingivalis OMVs. Through bioinformatics analysis and screening of target genes, chromobox 5 (CBX5) was identified as the downstream target of screened-out sRNA45033. Using a dual-luciferase reporter assay, overexpression, and knockdown methods, sRNA45033 was confirmed to target CBX5 to regulate hPDLC apoptosis. In addition, CUT&Tag (cleavage under targets and tagmentation) analysis confirmed the mechanism that CBX5 regulates apoptosis through the methylation of p53 DNA. Collectively, these findings indicate that the role of P. gingivalis OMVs is immunologically relevant and related to bacterial virulence during the development of periodontitis. IMPORTANCE P. gingivalis is a bacterium often associated with periodontitis. This study demonstrates that (i) sRNA45033 in P. gingivalis OMVs targets CBX5, (ii) CBX5 regulates the methylation of p53 DNA and its expression, which is associated with apoptosis, and (iii) a novel mechanism of interaction between hosts and pathogens is mediated by OMVs in the occurrence of periodontitis.

Human Umbilical Cord MSC Delivered-Soluble TRAIL Inhibits the Proliferation and Promotes Apoptosis of B-ALL Cell In Vitro and In Vivo.

The TNF-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of leukemic cells, while showed no cytotoxic effect on normal cells. One of the limitations for application of recombinant TRAIL (rhTRAIL) in leukemia treatment is that the serum half-life of this protein is short. Gene delivery is a good strategy to prolong the half-life of TRAIL. In this study, we genetically engineered umbilical cord-MSCs to continuously express and secrete soluble TRAIL (MSC-sTRAIL), to investigate the effects of MSC-sTRAIL on B-cell acute lymphocytic leukemia (B-ALL) cells. In vitro, MSC-sTRAIL significantly inhibited the proliferation of B-ALL cells by suppressing PI3K/AKT and MEK/ERK signaling pathways, and induced apoptosis of B-ALL cells via the caspase cascade-mediated pathway and mitochondrial-mediated pathway. In vivo, MSC-sTRAIL dramatically inhibited B-ALL cell growth. Meanwhile, B-ALL-induced splenic and renal injuries were significantly alleviated after MSC-sTRAIL treatment. Moreover, the serum levels of MSC-secreted sTRAIL were still high in MSC-sTRAIL treated mice, indicating an extended half-life of sTRAIL. Our study suggests that MSC delivered-TRAIL secretion is a potential therapeutic strategy for B-ALL treatment.

Polyphenols as Lung Cancer Chemopreventive Agents by Targeting microRNAs.

Lung cancer is the second leading cause of cancer-related death worldwide. In recent decades, investigators have found that microRNAs, a group of non-coding RNAs, are abnormally expressed in lung cancer, and play important roles in the initiation and progression of lung cancer. These microRNAs have been used as biomarkers and potential therapeutic targets of lung cancer. Polyphenols are natural and bioactive chemicals that are synthesized by plants, and have promising anticancer effects against several kinds of cancer, including lung cancer. Recent studies identified that polyphenols exert their anticancer effects by regulating the expression levels of microRNAs in lung cancer. Targeting microRNAs using polyphenols may provide a novel strategy for the prevention and treatment of lung cancer. In this review, we reviewed the effects of polyphenols on oncogenic and tumor-suppressive microRNAs in lung cancer. We also reviewed and discussed the potential clinical application of polyphenol-regulated microRNAs in lung cancer treatment.

The oral microbiome analysis reveals the similarities and differences between periodontitis and Crohn's disease-associated periodontitis.

Patients with Crohn's disease (CD) have higher incidences of oral diseases such as dental caries and periodontitis than healthy people. Studies indicate that the interaction between gut and oral microbiota is an important factor. To compare the composition and diversity of the oral microbiome in periodontitis and CD-associated periodontitis, subgingival plaque and saliva samples from patients with these diseases were collected for 16S rRNA gene sequencing analyses. In CD-associated periodontitis, the subgingival plaque had greater microbial diversity than saliva. Subgingival plaque had decreased abundances of Firmicutes, Streptococcus, and Haemophilus and increased abundances of Bacteroidetes, Actinomyces, Treponema_2, Capnocytophaga, and Porphyromonas relative to saliva. The microbial composition in subgingival plaque was similar between the two diseases. Both red complex (Porphyromonas, Tannerella, and Treponema) and orange complex (Fusobacteria) bacteria were abundant in periodontitis subgingival plaque, while orange complex bacteria (Prevotella_2 and Prevotella) were abundant in CD-associated periodontitis subgingival plaque. Pocket depth was significantly positively correlated with multiple periodontal pathogens, including Porphyromonas, Tannerella, and Treponema. This study reveals the similarities and differences in the oral microbiome between periodontitis and CD-associated periodontitis, which provides a foundation to further explore the associations between CD and periodontitis.

Current Understanding and Future Perspectives on Hyperprogressive Disease Highlight the Tumor Microenvironment.

Cancer immunotherapy with immune checkpoint inhibitors has revolutionized traditional cancer therapy. Although many patients have achieved long-term survival benefits from treatment with immune checkpoint inhibitors, there are still some patients who develop rapid tumor progression after immunotherapy, known as HPD. Here, we summarize the current knowledge on HPD after treatment with immune checkpoint inhibitors to promote a more thorough understanding of the disease. This review focuses on multiple aspects of HPD, especially the tumor microenvironment, with the hope that more reliable biomarkers and therapeutics will be established for HPD in the future.

Stretchable Conductive Fabric Enabled By Surface Functionalization of Commercial Knitted Cloth.

Textile-based stretchable electronic devices are one of the best candidates for future wearable applications, as they can simultaneously provide high compliance and wearing comfort to the human body. Stretchable conductive textile is the fundamental building block for constructing high-performance textile-based stretchable electronic devices. Here, we report a simple strategy for the fabrication of stretchable conductive fabric using commercial knitted cloth as a substrate. Briefly, we coated the fibers of the fabric with a thin layer of poly(styrene-block-butadiene-block-styrene) (SBS) by dip-coating. Then, silver nanoparticles (AgNPs) were loaded on the fabric by sequential absorption and in situ reduction. After loading AgNPs, the conductivity of the fabric could be as high as ∼800 S/m, while its maximal strain at break was higher than 540%. Meanwhile, such fabric also possesses excellent permeability, robust endurance to repeated stretching, long-time washing, and mechanical rubbing or tearing. We further approve that the fabric is less cytotoxic to mammalian skin and antibacterial to microbial, making it safe for on-skin applications. With these multifarious advantages, the fabric developed here is promising for on-skin wearable applications. As a proof-of-concept, we demonstrate its use as an electrode for collecting electrocardiograph signals and electrothermal therapy.

PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure.

Sevoflurane, one of the most commonly used anesthetic agents, has been demonstrated to induce widespread neurodegeneration in the developing brain. We aimed to evaluate the protective effects of a PDE-7 inhibitor (BRL-50481) against the neurotoxic effects of sevoflurane on the developing nervous system. Spatial learning and memory in sevoflurane-treated mice were examined using the Morris water maze test, and neuroprotective effects of PDE-7 inhibitor (BRL-50481) against sevoflurane-induced impairments were evaluated. Our results showed that sevoflurane treatment markedly induced neurodegeneration and impaired long-term memory in neonatal mice. Notably, BRL-50481 coadministration could significantly attenuate sevoflurane-induced learning and memory defects, prevent deterioration of recognition memory, and protect against neuron apoptosis. Mechanistically, BRL-50481 administration suppressed sevoflurane-induced neurodegenerative disorders through restoring cAMP and activating cAMP/CREB signaling in the hippocampus. PDE7 inhibitor may be a potential therapeutic agent for sevoflurane-induced neurodegeneration and long-term memory deficits.

[Clinical aesthetic effectiveness of restoring the subgingival residual crowns of anterior teeth with crown lengthening surgery].

PURPOSE: To evaluate the clinical effects of restoring the subgingival residual crowns of anterior teeth with periodontal and prosthodontics treatment. METHODS: Twenty-five patients with 28 subgingival residual crowns were treated by root canal therapy, crown lengthening surgery, and restored with post- core crown after 8 weeks. Changes in tooth mobility, gingival health were examined and clinical effect of crown restoration were evaluated at regular intervals of 1 month, 6 months and 12 months after restoration respectively. RESULTS: One year after restoration，the gingival health was improved and the overall effective rate was 89.28%. Three teeth were failed, one was due to mild tooth loose，and the other two were due to exposure of crown margin. CONCLUSIONS: For subgingival residual crowns of anterior teeth, crown lengthening surgery can conserve the biological width, and produce enough height of ferrule. Restoration can obtain satisfactory effects, but the indication must be selected properly.

[An epidemiological investigation of caries status of the first permanent molars of children aged 7-9 year in Taizhou City].

PURPOSE: To investigate caries prevalence of the first permanent molars of children aged 7-9 years in Taizhou city. METHODS: According to caries diagnostic criteria of WHO, 3653 primary school students in downtown areas of Taizhou city were surveyed; the data were statistically analyzed with SPSS 20.0 software package. RESULTS: The total caries prevalence rate of the first permanent molars was 24.99%. The average decayed-missing-filled (DMFT) teeth were 0.49.The total filling rate was 3.62%. The caries prevalence of the first permanent molars in 7-，8- and 9 year-old children was 15.37%,20.38% and 39.67%， respectively. The caries prevalence of girls was 27.61%, which was significantly higher than boys (21.84%).The caries prevalence (%) rate of the first permanent molars in the mandible was significantly higher than that in the maxilla. CONCLUSIONS: Caries prevalence of the first permanent molars is high in children aged 7-9 years in Taizhou city. Caries prevention and treatment measures should be strengthened for children in order to reduce the incidence of dental caries.