The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer.

BACKGROUND: The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis. METHODS AND RESULTS: In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α). CONCLUSIONS: These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.

Identification of a novel de novo mutation in SOX4 for syndromic tooth agenesis.

OBJECTIVES: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms. MATERIALS AND METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4. RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing. CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis. CLINICAL RELEVANCE: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.

Preparation of nanocellulose and its applications in wound dressing: A review.

Nanocellulose, as a nanoscale polymer material, has garnered significant attention worldwide due to its numerous advantages including excellent biocompatibility, thermal stability, non-toxicity, large specific surface area, and good hydrophilicity. Various methods can be employed for the preparation of nanocellulose. Traditional approaches such as mechanical, chemical, and biological methods possess their own distinct characteristics and limitations. However, with the growing deterioration of our living environment, several green and environmentally friendly preparation techniques have emerged. These novel approaches adopt eco-friendly technologies or employ green reagents to achieve environmental sustainability. Simultaneously, there is a current research focus on optimizing traditional nanocellulose preparation methods while addressing their inherent drawbacks. The combination of mechanical and chemical methods compensates for the limitations associated with using either method alone. Nanocellulose is widely used in wound dressings owing to its exceptional properties, which can accelerate the wound healing process and reduce patient discomfort. In this paper, the principle, advantages and disadvantages of each preparation method of nanocellulose and the research findings in recent years are introduced Moreover, this review provides an overview of the utilization of nanocellulose in wound dressing applications. Finally, the prospective trends in its development alongside corresponding preparation techniques are discussed.

Medrysone promotes corneal injury repair by promoting M2-like polarization of macrophages.

BACKGROUND: Accumulated evidence suggests that M2-like polarized macrophages plays an important role in reducing inflammation, promoting and accelerating wound healing process and tissue repair. Thus, M2-like TAMs (Tumour-associated macrophages) was an appealing target for therapy intervention. METHOD: Flow cytometry and RT-PCR assay were used to detect the polarization of macrophages induced by Medrysone, and the rat corneal mechanical injury model was established to evaluate the efficacy of Medrysone in cornel repair. RESULTS: Here we found that Medrysone enhanced IL-4 induced M2 polarization of macrophages, as illustrated by increased expression of CD206, up-regulation of M2 marker mRNAs. Medrysone promoted VEGF and CCL2 secretion in IL-4 induced M2-like polarization. IL-4 triggered STAT6 activation was further enhanced by Medrysone and silencing of STAT6 partially abrogated the stimulatory effect of Medrysone. Medrysone improved migration-promoting feature of M2-like macrophages, as indicated by increased migration of endothelial cells. Further, Medrysone promoted corneal injury repair by inducing M2 polarization of macrophages in vivo. CONCLUSION: Our study suggest that Medrysone promotes corneal injury repair by inducing the M2 polarization of macrophages, providing a theoretical basis for the application of Medrysone in the treatment of corneal injury.

Altered salivary microbiota profile in patients with abdominal aortic aneurysm.

Evidence suggests that the DNA of oral pathogens is detectable in the dilated aortic tissue of abdominal aortic aneurysm (AAA), one of the most fatal cardiovascular diseases. However, the association between oral microbial homeostasis and aneurysm formation remains largely unknown. In this study, a cohort of individuals, including 53 AAA patients and 30 control participants (CTL), was recruited for salivary microbiota investigation by 16S rRNA gene sequencing and bioinformatics analysis. Salivary microbial diversity was decreased in AAA compared with CTL, and the microbial structures were significantly separated between the two groups. Additionally, significant taxonomic and functional changes in the salivary microbiota of AAA participants were observed. The genera Streptococcus and Gemella were remarkably enriched, while Selenomonas, Leptotrichia, Lautropia and Corynebacterium were significantly depleted in AAA. Co-occurrence network analysis showed decreased potential interactions among the differentially abundant microbial genera in AAA. A machine-learning model predicted AAA using the combination of 5 genera and 14 differentially enriched functional pathways, which could distinguish AAA from CTL with an area under the receiver-operating curve of 90.3 %. Finally, 16 genera were found to be significantly positively correlated with the morphological parameters of AAA. Our study is the first to show that AAA patients exhibit oral microbial dysbiosis, which has high predictive power for AAA, and the over-representation of specific salivary bacteria may be associated with AAA disease progression. Further studies are needed to better understand the function of putative oral bacteria in the etiopathogenesis of AAA. Importance: Host microbial dysbiosis has recently been linked to AAA as a possible etiology. To our knowledge, studies of the oral microbiota and aneurysms remain scarce, although previous studies have indicated that the DNA of some oral pathogens is detectable in aneurysms by PCR method. We take this field one step further by investigating the oral microbiota composition of AAA patients against control participants via high-throughput sequencing technologies and unveiling the potential microbial biomarker associated with AAA formation. Our study will provide new insights into AAA etiology, treatment and prevention from a microecological perspective and highlight the effects of oral microbiota on vascular health.

Oral pathogens exacerbate Parkinson's disease by promoting Th1 cell infiltration in mice.

BACKGROUND: Parkinson's disease (PD) is a common chronic neurological disorder with a high risk of disability and no cure. Periodontitis is an infectious bacterial disease occurring in periodontal supporting tissues. Studies have shown that periodontitis is closely related to PD. However, direct evidence of the effect of periodontitis on PD is lacking. Here, we demonstrated that ligature-induced periodontitis with application of subgingival plaque (LIP-SP) exacerbated motor dysfunction, microglial activation, and dopaminergic neuron loss in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. RESULTS: The 16S rRNA gene sequencing revealed that LIP-SP induced oral and gut dysbiosis. Particularly, Veillonella parvula (V. parvula) and Streptococcus mutans (S. mutans) from oral ligatures were increased in the fecal samples of MPTP + LIP-SP treated mice. We further demonstrated that V. parvula and S. mutans played crucial roles in LIP-SP mediated exacerbation of motor dysfunction and neurodegeneration in PD mice. V. parvula and S. mutans caused microglial activation in the brain, as well as T helper 1 (Th1) cells infiltration in the brain, cervical lymph nodes, ileum and colon in PD mice. Moreover, we observed a protective effect of IFNγ neutralization on dopaminergic neurons in V. parvula- and S. mutans-treated PD mice. CONCLUSIONS: Our study demonstrates that oral pathogens V. parvula and S. mutans necessitate the existence of periodontitis to exacerbate motor dysfunction and neurodegeneration in MPTP-induced PD mice. The underlying mechanisms include alterations of oral and gut microbiota, along with immune activation in both brain and peripheral regions. Video Abstract.

Predictors of progression in idiopathic inflammatory myopathies with interstitial lung disease.

The idiopathic inflammatory myopathies (IIMs) are a group of connective tissue diseases that afect multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the most common and heterogeneous complication of IIMs, with its degree ranging from mild to fatal. Thus, it is critical to identify clinical features and validated biomarkers for predicting disease progression and prognosis, which could be beneficial for therapy adjustment. In this review, we discuss predictors for rapid progression of IIM-ILD and propose guidance for disease monitoring and implications of therapy. Systematic screening of myositis-specific antibodies, measuring serum biomarker levels, pulmonary function tests, and chest high-resolution computer tomography will be beneficial for the evaluation of disease progression and prognosis.

Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer.

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

Two-Stage Multi-Channel Fault Detection and Remaining Useful Life Prediction Model of Internal Gear Pumps Based on Robust-ResNet.

The internal gear pump is simple in structure, small in size and light in weight. It is an important basic component that supports the development of hydraulic system with low noise. However, its working environment is harsh and complex, and there are hidden risks related to reliability and exposure of acoustic characteristics over the long term. In order to meet the requirements of reliability and low noise, it is very necessary to make models with strong theoretical value and practical significant to accurately monitor health and predict the remaininglife of the internal gear pump. This paper proposed a multi-channel internal gear pump health status management model based on Robust-ResNet. Robust-ResNet is an optimized ResNet model based on a step factor h in the Eulerian approach to enhance the robustness of the ResNet model. This model was a two-stage deep learning model that classified the current health status of internal gear pumps, and also predicted the remaining useful life (RUL) of internal gear pumps. The model was tested in an internal gear pump dataset collected by the authors. The model was also proven to be useful in the rolling bearing data from Case Western Reserve University (CWRU). The accuracy results of health status classification model were 99.96% and 99.94% in the two datasets. The accuracy of RUL prediction stage in the self-collected dataset was 99.53%. The results demonstrated that the proposed model achieved the best performance compared to other deep learning models and previous studies. The proposed method was also proven to have high inference speed; it could also achieve real-time monitoring of gear health management. This paper provides an extremely effective deep learning model for internal gear pump health management with great application value.

Periodontitis exacerbates atherosclerosis through Fusobacterium nucleatum-promoted hepatic glycolysis and lipogenesis.

AIMS: Positive associations between periodontitis (PD) and atherosclerosis have been established, but the causality and mechanisms are not clear. We aimed to explore the causal roles of PD in atherosclerosis and dissect the underlying mechanisms. METHODS AND RESULTS: A mouse model of PD was established by ligation of molars in combination with application of subgingival plaques collected from PD patients and then combined with atherosclerosis model induced by treating atheroprone mice with a high-cholesterol diet (HCD). PD significantly aggravated atherosclerosis in HCD-fed atheroprone mice, including increased en face plaque areas in whole aortas and lesion size at aortic roots. PD also increased circulating levels of triglycerides and cholesterol, hepatic levels of cholesterol, and hepatic expression of rate-limiting enzymes for lipogenesis. Using 16S ribosomal RNA (rRNA) gene sequencing, Fusobacterium nucleatum was identified as the most enriched PD-associated pathobiont that is present in both the oral cavity and livers. Co-culture experiments demonstrated that F. nucleatum directly stimulated lipid biosynthesis in primary mouse hepatocytes. Moreover, oral inoculation of F. nucleatum markedly elevated plasma levels of triglycerides and cholesterol and promoted atherogenesis in HCD-fed ApoE-/- mice. Results of RNA-seq and Seahorse assay indicated that F. nucleatum activated glycolysis, inhibition of which by 2-deoxyglucose in turn suppressed F. nucleatum-induced lipogenesis in hepatocytes. Finally, interrogation of the molecular mechanisms revealed that F. nucleatum-induced glycolysis and lipogenesis by activating PI3K/Akt/mTOR signalling pathway in hepatocytes. CONCLUSIONS: PD exacerbates atherosclerosis and impairs lipid metabolism in mice, which may be mediated by F. nucleatum-promoted glycolysis and lipogenesis through PI3K/Akt/mTOR signalling in hepatocytes. Treatment of PD and specific targeting of F. nucleatum are promising strategies to improve therapeutic effectiveness of hyperlipidaemia and atherosclerosis.

Roles of oral microbiota and oral-gut microbial transmission in hypertension.

INTRODUCTION: Considerable evidence has linked periodontitis (PD) to hypertension (HTN), but the nature behind this connection is unclear. Dysbiosis of oral microbiota leading to PD is known to aggravate different systematic diseases, but the alteration of oral microbiota in HTN and their impacts on blood pressure (BP) remains to be discovered. OBJECTIVES: To characterize the alterations of oral and gut microbiota and their roles in HTN. METHODS: We performed a cross-sectional (95 HTN participants and 39 controls) and a 6-month follow-up study (52 HTN participants and 26 controls) to analyze the roles of oral and gut microbiota in HTN. Saliva, subgingival plaques, and feces were collected for 16S rRNA gene sequencing or metagenomic analysis. C57BL/6J mice were pretreated with antibiotics to deplete gut microbiota, and then transplanted with human saliva by gavage to test the impacts of abnormal oral-gut microbial transmission on HTN. RESULTS: BP in participants with PD was higher than no PD in both cross-sectional and follow-up cohort. Relative abundances of 14 salivary genera, 15 subgingival genera and 10 gut genera significantly altered in HTN and those of 7 salivary genera, 12 subgingival genera and 6 gut genera significantly correlated with BP. Sixteen species under 5 genera were identified as oral-gut transmitters, illustrating the presence of oral-gut microbial transmission in HTN. Veillonella was a frequent oral-gut transmitter stably enriched in HTN participants of both cross-sectional and follow-up cohorts. Saliva from HTN participants increased BP in hypertensive mice. Human saliva-derived Veillonella successfully colonized in mouse gut, more abundantly under HTN condition. CONCLUSIONS: PD and oral microbiota are strongly associated with HTN, likely through oral-gut transmission of microbes. Ectopic colonization of saliva-derived Veillonella in the gut may aggravate HTN. Therefore, precise manipulations of oral microbiota and/or oral-gut microbial transmission may be useful strategies for better prevention and treatment of HTN.

Reduced Adenoma Miss Rate With 9-Minute vs 6-Minute Withdrawal Times for Screening Colonoscopy: A Multicenter Randomized Tandem Trial.

INTRODUCTION: Although the 9-minute mean withdrawal time (m-WT) is often reported to be associated with the optimal adenoma detection rate (ADR), no randomized trials of screening colonoscopy have confirmed the impact of a 9-minute m-WT on adenoma miss rate (AMR) and ADR. METHODS: A multicenter tandem trial was conducted in 11 centers. Seven hundred thirty-three asymptomatic participants were randomized to receive segmental tandem screening colonoscopy with a 9-minute withdrawal, followed by a 6-minute withdrawal (9-minute-first group, 9MF, n = 366) or vice versa (6-minute-first group, 6MF, n = 367). The primary outcome was the lesion-level AMR. RESULTS: The intention-to-treat analysis revealed that 9MF significantly reduced the lesion-level (14.5% vs 36.6%, P < 0.001) and participant-level AMR (10.9% vs 25.9%, P < 0.001), advanced adenoma miss rate (AAMR, 5.3% vs 46.9%, P = 0.002), multiple adenomas miss rate (20.7% vs 56.5%, P = 0.01), and high-risk adenomas miss rate (14.6% vs 39.5%, P = 0.01) of 6MF without compromising detection efficiency ( P = 0.79). In addition, a lower false-negative rate for adenomas ( P = 0.002) and high-risk adenomas ( P < 0.05), and a lower rate of shortening surveillance schedule ( P < 0.001) were also found in 9MF, accompanying with an improved ADR in the 9-minute vs 6-minute m-WT (42.3% vs 33.5%, P = 0.02). The independent inverse association between m-WT and AMR remained significant even after adjusting ADR, and meanwhile, 9-minute m-WT was identified as an independent protector for AMR and AAMR. DISCUSSION: In addition to increasing ADR, 9-minute m-WT also significantly reduces the AMR and AAMR of screening colonoscopy without compromising detection efficiency.

Characteristics and Correlations of the Oral and Gut Fungal Microbiome with Hypertension.

The mycobiome is an essential constituent of the human microbiome and is associated with various diseases. However, the role of oral and gut fungi in hypertension (HTN) remains largely unexplored. In this study, saliva, subgingival plaques, and feces were collected from 36 participants with HTN and 24 healthy controls for metagenomic sequencing. The obtained sequences were analyzed using the Kraken2 taxonomic annotation pipeline to assess fungal composition and diversity. Correlations between oral and gut fungi and clinic parameters, between fungi within the same sample types, and between different sample types were identified by Spearman's correlation analysis. Overall, the subgingival fungal microbiome had substantially higher alpha diversity than the salivary and fecal fungal microbiomes. The fungal microbiomes of the three sample types displayed distinct beta diversity from each other. Oral fungi but not gut fungi in HTN had beta diversity significantly different from that of controls. Among the fungi shared in the oral cavity and gut, Exophiala was the genus with the most notable changes. Exophiala spinifera was the most abundant salivary species in HTN. Some fungal species directly correlated with blood pressure, including gut Exophiala xenobiotica and Exophiala mesophila. The markedly impaired ecological cocorrelation networks of oral and gut fungi in HTN suggested compromised association among fungal species. Most fungi were shared in the oral cavity and gut, and their correlations suggested the potential interplays between oral and gut fungi. In conclusion, the oral cavity and intestine have unique fungal ecological environments. The fungal enrichment and ecology in HTN, the correlations between oral and gut fungi, and the associations between oral and gut fungi and clinical parameters suggest an important role that the fungal microbiome may play in HTN. IMPORTANCE Our study fills the gap in human studies investigating the oral and gut fungal microbiota in association with blood pressure. It characterizes the diversity and composition of the oral and gut fungal microbiome in human subjects, elucidates the dysbiosis of fungal ecology in a hypertensive population, and establishes oral-gut fungal correlations and fungus-clinical parameter correlations. Targeting fungi in the oral cavity and/or gut may provide novel strategies for the prevention and treatment of hypertension.

Exosomes derived from stem cells from apical papilla promote angiogenesis via miR-126 under hypoxia.

OBJECTIVES: To explore the effect of exosomal miR-126 derived from stem cells from the apical papilla (SCAPs) under hypoxia on human umbilical vein endothelial cell (HUVEC) angiogenesis. METHODS: miR-126 mimics plasmids were used to upregulate miR-126 in SCAPs. Internalization of PKH26-labeled exosomes was examined by fluorescent microscopy. CCK-8 assay, Transwell assay, scratch assay, tube formation assay, and Matrigel plug assay were performed to detect the effects of exosomes on the angiogenic ability of HUVECs. The luciferase reporter assay and rescue assay were performed to examine the relationship between miR-126 and sprouty-related, EVH1 domain-containing protein 1 (SPRED1). The involvement of SPRED1 and the extracellular signal-regulated kinase (ERK) signaling pathway was evaluated by western blotting. RESULTS: miR-126 expression was upregulated in SCAPs and in SCAP-derived exosomes under hypoxia. miR-126 expression was increased in HUVECs when cocultured with SCAP-derived exosomes. Induced overexpression of miR-126 in hypoxic SCAPs and secreted exosomes resulted in enhanced angiogenesis both in vitro and in vivo. Western blot analysis revealed that miR-126-mediated SPRED1 downregulation induced activation of ERK signaling. CONCLUSIONS: Under hypoxic conditions, exosomes derived from SCAPs can promote HUVEC angiogenesis through expression of miR-126, which subsequently suppresses SPRED1 and activates the ERK signaling pathway.

Coping and post-traumatic stress disorder symptoms among Chinese youth in the peak and remission periods of COVID-19.

The COVID-19 pandemic has exposed emergent vulnerability to adolescents' mental health. This longitudinal study investigated the association between coping at the peak of the COVID outbreak (T1) and Post-Traumatic Stress Disorder (PTSD) symptoms concurrently, and at the remission periods of COVID in China three months (T2) and six months (T3) later in a sample of 6th to 12th-grade students (N = 782). The results showed that forward-focus coping was negatively associated with PTSD symptoms across all three timepoints and predicted reduced risk for more PTSD symptoms at T2, and trauma-focus coping was positively associated with PTSD symptoms across all three timepoints and predicted higher risk of PTSD symptoms both at T2 and T3. There was an interaction effect of trauma-focus coping and T1 symptoms on later symptoms (T3) - trauma-focus coping was more detrimental for those who had more initial symptoms. The results showed the beneficial effects of future-oriented coping and harmful effects of trauma-focus coping for Chinese youth during the epidemic. Clinical implications of the results were discussed.

The Integrated Study on the Chemical Profiling to Explore the Constituents and Mechanism of Traditional Chinese Medicine Preparation Huatuo Jiuxin Pills Based on UPLC-Q-TOF/MSE and Network Pharmacology.

Huatuo Jiuxin Pills (HJP), a traditional Chinese medicine (TCM) preparation, has been widely used to treat Cardiovascular Diseases (CVDs) for more than 20 years. However, there were still gaps in the study of chemical components and potential pharmacological effects in the HJP. In this study, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MSE) combined with network pharmacology was used to comprehensively explore the chemical components in HJP and explore its potential active compounds and the mechanism for the treatment of CVDs. A total of 117 compounds, mainly including saponins, cholic acids, and bufadienolides, were rapidly identified and characterized. Simultaneously, the fragmentation mode and characteristic ion analysis of different types of representative compounds were carried out. Network pharmacology results showed that the more important active ingredients mainly include 5ß-hydroxybufotalin, 19 oxo-cinobufagin, bufarenogin, etc. While, the main targets were PIK3CA, MAPK1, VEGFA and so on. Importantly, HJP has therapeutic effects on CVDs by acting on endocrine resistance, PI3K-Akt signaling pathway, HIF-1 signaling pathway, etc. In addition, molecular docking results showed that the core active ingredients with higher degrees in HJP have a strong affinity with the core targets of CVDs. The current work fills the gap in the chemical substance basis of HJP, and also facilitates a better understanding of the effective components, therapeutic targets, and signaling pathways of HJP in the treatment of CVDs.

A case study: a continuous improvement project of lecturing skills for clinical teachers in Chinese residency standardized training.

BACKGROUND: Aiming at the poor quality of small lectures due to the lack of lecturing skills of the clinical teachers in residency standardized training, the Teaching and Training Department of Shanghai East Hospital set up a continuous improvement project of lecturing skills for the clinical teachers to search for effective ways to improve lecture quality, then the effect was evaluated. METHODS: Based on the ADDIE model of training design, the department conducted the project in accordance with a process of analysis, design, development, implementation and evaluation. A special course "Clinical Teacher Presentation Training" (CTPT) was developed to convey and train the 5 key behaviors in presentation to improving lecture quality of the clinical teachers. Ninety-nine clinical teachers who give lectures to the residents were recruited as subjects for the project. Adopted the model of "intensive training + practice transference" to strengthen lecturing skills, and applied the Kirkpatrick Four Levels to evaluate the effect of the project from multi-role and multi-stage. RESULTS: The training satisfaction of the CTPT course from the subjects reaches 100%. The subjects have a high degree of knowledge acquisition through CTPT and the knowledge of the 5 key behaviors has been actually used in their lectures at the stage of practice transference. Comparing the data before training and after transference, it is found that the average increasing of the subjects' 5 key behavior scores made by teaching secretaries is 14.12 points (14.12%) and that of the subjects' self-efficacy scores is 9.31 points (9.31%); the performance values were modeling based on the scores from different types of evaluators and increased by an average of 12.61 points (12.61%); and the star ratings of the overall performance increased by an average of 1.17 points (23.4%). The results showed statistically difference (P < 0.001). CONCLUSIONS: The project effectively promoted the improvement of the clinical teachers' lecturing skills and the quality of small lectures.

microRNA-126 inhibits vascular cell adhesion molecule-1 and interleukin-1beta in human dental pulp cells.

BACKGROUND: Vascular cell adhesion molecule (VCAM-1) mediates pulpitis via regulating interleukin (IL)-1ß. microRNA (miR)-126 was reported to regulate the VCAM-1 under many different pathophysiological circumstances. We investigated variations of miR-126 and VCAM-1 in inflamed patient pulp tissues and determined potential roles of miR-126 in pulpitis using human dental pulp cells (hDPCs) in vitro. METHODS: We quantitatively measured the transcripts of miR-126 and VCAM-1 in inflamed human pulp tissues using qRT-PCR and compared with those from healthy human pulp tissues. In addition, we transfected miR-126 in hDPCs using plasmid DNA (pDNA)-encoding miR-126 delivered by polyethylenimine (PEI) nanoparticles. RESULTS: The irreversible pulpitis significantly reduced miR-126 and increased the transcript of VCAM-1 in pulp tissues (p < 0.05). pDNA-encoding miR-126 delivered PEI nanoparticles and effectively upregulated the expression of miR-126 in hDPCs (p < 0.05). The overexpression of miR-126 could effectively suppress the transcripts and protein levels of VCAM-1 and IL-1ß induced by Pg-LPS at 100ng/mL in DPCs (p < 0.05). CONCLUSIONS: miR-126 is involved in pulpitis and downregulated the VCAM-1 and IL-1ß in DPCs. miR-126 may be a potential target to attenuate the inflammation of pulpitis.

Silicate bioceramics elicit proliferation and odonto-genic differentiation of human dental pulp cells.

This study aimed to investigate the effects of silicates on the proliferation and odontogenic differentiation of human dental pulp cells (hDPCs) in vitro. HDPCs were cultured in the presence of calcium silicate (CS) extracts, while calcium hydroxide (CH) extracts and culture medium without CH or CS were used as the control groups. The calcium and phosphorus ion concentrations in the CS were similar to those in the control groups, but the concentration of silicon ions in the CS extracts was higher than that in the control groups. HDPCs cultured with CS and CH extracts at dilution of 1/128 proliferated significantly more than those cultured with the control treatments. CS extracts promoted cell migration, enhanced the expression of odontogenic marker genes and conspicuously increased odontogenesis-related protein production and the release of cytokines, suggesting that CS bioactive ceramics possess excellent biocompatibility and bioactivity and have the potential for application as pulp-capping agents.

Endoplasmic reticulum stress response mediated by the PERK-eIF2α-ATF4 pathway is involved in odontoblastic differentiation of human dental pulp cells.

OBJECTIVE: RNA-activated protein kinase-like ER-resident kinase (PERK) was a major transducer of Endoplasmic reticulum (ER) stress response and it directly phosphorylated α-subunit of eukaryotic initiation factor 2 (eIF2α), which specifically promoted the translation of activating transcription factor 4 (ATF4), an important transcription factor in cells' differentiation. The purpose of this study was to establish whether ER stress mediated by PERK-eIF2α-ATF4 pathway was involved in odontoblastic differentiation of human dental pulp cells (DPCs). METHODS: DPCs were isolated from extracted teeth and cultured in odontogenic medium. A recombinant lentiviral vector was constructed to transfect DPCs for PERK knockdown. Alkaline phosphatase (ALP) and Alizarin red S staining were used to characterize the odontoblastic differentiation. Real-time polymerase chain reactions (RT-PCR) were performed to analyze the genes' expressions in DPCs' odontoblastic differentiation. The mRNA and protein levels of ER stress markers were examined by RT-PCR and western blot. RESULTS: DPCs cultured in odontogenic media showed increased ALP activity and mineralized nodule formation. Notably, treatment with differentiation medium resulted in the up-regulation of genes, such as osteocalcin (OCN), bone sialoprotein (BSP), dentin sialophosphoprotein (DSPP), splicing x-box binding protein-1 (sXBP1), ATF4 and glucose-regulated protein 78 (GRP78). Meanwhile, the expressions of PERK-eIF2α-ATF4 pathway proteins, phosphorylated PERK, phosphorylated eIF2α and ATF4, increased in odontoblastic induction cells compared with controls. Furthermore, inhibition of PERK (PERK knockdown) decreased ALP activity and matrix mineralization in DPCs accompanied by the decrease expression of phosphorylated eIF2α and ATF4. CONCLUSION: These results suggested that PERK-eIF2α-ATF4 pathway was involved in the odontoblastic differentiation of DPCs.