METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53-wild-type cells.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.

Glycaemia risk index uncovers distinct glycaemic variability patterns associated with remission status in type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this work was to define a unique remission status using glycaemia risk index (GRI) and other continuous glucose monitoring (CGM) metrics in individuals with type 1 diabetes for improved phenotyping. METHODS: A group of 140 individuals with type 1 diabetes were recruited for a cross-sectional study. The participants were categorised into four groups based on their remission status, which was defined as insulin-dose-adjusted A1c (IDAA1c) <9 or C-peptide ≥300 pmol/l: new-onset (n=24); mid-remission (n=44); post-remission (n=44); and non-remission (individuals who did not experience remission, n=28). Participants in the remission phase were referred to as 'remitters', while those who were not in the remission phase were referred to as 'non-remitters', the latter group including new-onset, post-remission and non-remission participants. Clinical variables such as HbA1c, C-peptide and insulin daily dose, as well as IDAA1C and CGM data, were collected. The patterns of CGM metrics were analysed for each group using generalised estimating equations to investigate the glycaemic variability patterns associated with remission status. Then, unsupervised hierarchical clustering was used to place the participants into subgroups based on GRI and other CGM core metrics. RESULTS: The glycaemic variability patterns associated with remission status were found to be distinct based on the circadian CGM metrics. Remitters showed improved control of blood glucose levels over 14 days within the range of 3.9-10 mmol/l, and lower GRI compared with non-remitters (p<0.001). Moreover, GRI strongly correlated with IDAA1C (r=0.62; p<0.001) and was sufficient to distinguish remitters from non-remitters. Further, four subgroups demonstrating distinct patterns of glycaemic variability associated with different remission status were identified by clustering on CGM metrics: remitters with low risk of dysglycaemia; non-remitters with high risk of hypoglycaemia; non-remitters with high risk of hyperglycaemia; and non-remitters with moderate risk of dysglycaemia. CONCLUSIONS/INTERPRETATION: GRI, an integrative index, together with other traditional CGM metrics, helps to identify different glycaemic variability patterns; this might provide specifically tailored monitoring and management strategies for individuals in the various subclusters.

Designing 3d Transition Metal Cation-Doped MRuOx As Durable Acidic Oxygen Evolution Electrocatalysts for PEM Water Electrolyzers.

The continuous dissolution and oxidation of active sites in Ru-based electrocatalysts have greatly hindered their practical application in proton exchange membrane water electrolyzers (PEMWE). In this work, we first used density functional theory (DFT) to calculate the dissolution energy of Ru in the 3d transition metal-doped MRuOx (M = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) to evaluate their stability for acidic oxygen evolution reaction (OER) and screen out ZnRuOx as the best candidate. To confirm the theoretical predictions, we experimentally synthesized these MRuOx materials and found that ZnRuOx indeed displays robust acidic OER stability with a negligible decay of η10 after 15 000 CV cycles. Of importance, using ZnRuOx as the anode, the PEMWE can run stably for 120 h at 200 mA cm-2. We also further uncover the stability mechanism of ZnRuOx, i.e., Zn atoms doped in the outside of ZnRuOx nanocrystal would form a "Zn-rich" shell, which effectively shortened average Ru-O bond lengths in ZnRuOx to strengthen the Ru-O interaction and therefore boosted intrinsic stability of ZnRuOx in acidic OER. In short, this work not only provides a new study paradigm of using DFT calculations to guide the experimental synthesis but also offers a proof-of-concept with 3d metal dopants as RuO2 stabilizer as a universal principle to develop high-durability Ru-based catalysts for PEMWE.

CXCL12-CXCR4 mediates CD57+ CD8+ T cell responses in the progression of type 1 diabetes.

CD57+ CD8+ T cells, also referred as effector memory cells, are implicated in various conditions including tumor immunity, virus immunity, and most recently with autoimmunity. However, their roles in the progression and remission of T1D are still unclear. Here, we noted an increase in peripheral CD57+ CD8+ T cells in a T1D patient harboring an activator of transcription 3 (STAT3) mutation. Our in-depth study on the role of CD57+ CD8+ T cells within a T1D patient cohort revealed that these cells undergo significant compositional shifts during the disease's progression. Longitudinal cohort data suggested that CD57+ CD8+ T cell prevalence may be a harbinger of ß-cell function decline in T1D patients. Characterized by robust cytotoxic activity, heightened production of pro-inflammatory cytokines, and increased intracellular glucose uptake, these cells may be key players in the pathophysiology of T1D. Moreover, in vitro assays showed that the CXCL12-CXCR4 axis promotes the expansion and function of CD57+ CD8+ T cells via Erk1/2 signaling. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57+ CD8+ T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57+ CD8+ T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

A new artificial intelligence system for both stomach and small bowel capsule endoscopy.

BACKGROUND AND AIMS: Despite the benefits of artificial intelligence (AI) in small bowel (SB) capsule endoscopy (CE) image reading, information on its application in the stomach and SB CE is lacking. METHODS: In this multicenter, retrospective diagnostic study, gastric imaging data were added to the deep learning (DL)-based SmartScan (SS), which has been described previously. A total of 1,069 magnetically controlled gastrointestinal (GI) CE examinations (comprising 2,672,542 gastric images) were used in the training phase for recognizing gastric pathologies, producing a new AI algorithm named SS Plus. 342 fully automated, magnetically controlled CE (FAMCE) examinations were included in the validation phase. The performance of both senior and junior endoscopists with both the SS Plus-Assisted Reading (SSP-AR) and conventional reading (CR) modes was assessed. RESULTS: SS Plus was designed to recognize 5 types of gastric lesions and 17 types of SB lesions. SS Plus reduced the number of CE images required for review to 873.90 (1000) (median, IQR 814.50-1,000) versus 44,322.73 (42,393) (median, IQR 31,722.75-54,971.25) for CR. Furthermore, with SSP-AR, endoscopists took 9.54 min (8.51) (median, IQR 6.05-13.13) to complete the CE video reading. In the 342 CE videos, SS Plus identified 411 gastric and 422 SB lesions, whereas 400 gastric and 368 intestinal lesions were detected with CR. Moreover, junior endoscopists remarkably improved their CE image reading ability with SSP-AR. CONCLUSIONS: Our study shows that the newly upgraded DL-based algorithm SS Plus can detect GI lesions and help improve the diagnostic performance of junior endoscopists in interpreting CE videos.

Synthesis and antitumor activities of novel 3-(6-aminopyridin-3-yl)benzamide derivatives: Inducing cell cycle arrest and apoptosis via AURKB transcription inhibition.

Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC50 value of 0.04 ± 0.01 µM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.

Construction of a prediction model for pulmonary infection and its risk factors in Intensive Care Unit patients.

Objective: To identify independent risk factors of pulmonary infection in intensive care unit (ICU) patients, and to construct a prediction model. Methods: Medical data of 398 patients treated in the ICU of Jiaxing Hospital of Traditional Chinese Medicine from January 2019 to January 2023 were analyzed. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for pulmonary infection in ICU patients. R software was used to construct a nomogram prediction model, and the prediction model was internally validated using computer simulation bootstrap method. Predictive value of the model was analyzed using the receiver operating characteristic (ROC) curve. Results: A total of 97 ICU patients (24.37%) developed pulmonary infection. Age, ICU stay time, invasive operation, diabetes, duration of mechanical ventilation, and state of consciousness were all identified as risk factors for pulmonary infection. The calibration curve of the constructed nomogram prediction model showed a good consistency between the predicted value of the model and the actual observed value. ROC curve analysis showed that the area under the curve (AUC) of the model was 0.784 (95% CI: 0.731-0.837), indicating a certain predictive value. Conclusions: Age, length of stay in ICU, invasive operation, diabetes, duration of mechanical ventilation, and state of consciousness are risk factors for pulmonary infection in ICU patients. The nomogram prediction model constructed based on the above risk factors has shown a good predictive value.

Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes.

AIMS/HYPOTHESIS: Notwithstanding the irreversible beta cell failure seen in type 1 diabetes, some individuals may experience a special phase named 'partial remission' or 'the honeymoon period', in which there is a transient recovery of beta cell function. Importantly, this stage of partial remission shows spontaneous immune downregulation, although the exact mechanisms are unclear. Intracellular energy metabolism is crucial for the differentiation and function of T cells, and provides promising targets for immunometabolic intervention strategies, but its role during partial remission is unknown. In this study, we aim to investigate the association between T cell intracellular glucose and fatty acid metabolism and the partial remission phase. METHODS: This is a cross-sectional study with a follow-up component. Intracellular uptake of glucose and fatty acids by T cells was detected in participants with either new-onset type 1 diabetes or type 1 diabetes that was already in partial remission, and compared with heathy individuals and participants with type 2 diabetes. Subsequently, the participants with new-onset type 1 diabetes were followed up to determine whether they experienced a partial remission (remitters) or not (non-remitters). The trajectory of changes in T cell glucose metabolism was observed in remitters and non-remitters. Expression of programmed cell death-1 (PD-1) was also analysed to investigate possible mechanisms driving altered glucose metabolism. Partial remission was defined when patients had convalescent fasting or 2 h postprandial C-peptide >300 pmol/l after insulin treatment. RESULTS: Compared with participants with new-onset type 1 diabetes, intracellular glucose uptake by T cells decreased significantly in individuals with partial remission. The trajectory of these changes during follow-up showed that intracelluar glucose uptake in T cells fluctuated during different disease stages, with a decreased uptake during partial remission that rebounded after remission. This dynamic in T cell glucose uptake was only detected in remitters and not in non-remitters. Further analysis demonstrated that changes of intracellular glucose uptake were found in subsets of CD4+ and CD8+ T cells, including Th17, Th1, CD8+ naive T cells (Tn) and CD8+ terminally differentiated effector memory T cells (Temra). Moreover, glucose uptake in CD8+ T cells was negatively related to PD-1 expression. The intracellular metabolism of fatty acids was not found to be different between new-onset participants and those in partial remission. CONCLUSIONS/INTERPRETATION: Intracellular glucose uptake in T cells was specifically decreased during partial remission in type 1 diabetes and may be related to PD-1 upregulation, which may be involved in the down-modulation of immune responses during partial remission. This study suggests that altered immune metabolism could be a target for interventions at the point of diagnosis of type 1 diabetes.

Structure optimization, synthesis, and biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H)-one derivatives as potential multi-targeted anticancer agents via Aurora A/ PI3K/BRD4 inhibition.

Aurora A (Aurora kinase A), a critical regulator of cell mitosis, is frequently overexpressed in many malignant cancers, and has been considered as a promising drug target for cancer therapy. Likewise, Phosphatidylinositol 3-kinase alpha (PI3Kα) is also regarded as one of the most important targets in cancer therapy by mediating the cell growth and angiogenesis of various human cancers. In addition, Bromodomain-containing protein 4 (BRD4) modulates oncogene expressions of Myc, Aurora kinase and various RTKs. Recently, accumulating evidences indicated that hyperactivated or abnormally expressed Aurora A, PI3Kα or BRD4 are closely associated with drug resistance and poor prognosis of non-small cell lung cancer (NSCLC). Hence, simultaneous inhibition of Aurora A, PI3Kα, and BRD4 is expected to be a new strategy for NSCLC therapy. In this study, we performed further structure optimization of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H) -one based on previous study to obtain a series of derivatives for discovering potential Aurora A, PI3Kα and BRD4 multi-targeted inhibitors. MTT assay showed that most of the newly synthesized compounds exhibited an evident anticancer activity against the NSCLC cells. Among them, the IC50 values of the most potent compound 9a were 0.83, 0.26 and 1.02 µM against A549, HCC827 and H1975 cells, respectively. In addition, 9a markedly inhibited the Aurora A and PI3Kα kinase activities with IC50 values of 10.19 nM and 13.12 nM. Compound 9a induced G2/M phase arrests and apoptosis of HCC827 cells by simultaneous inhibition of Aurora A/PI3K/ BRD4 signaling pathways. Collectively, our studies suggested that 9a might be a potential multi-targeted inhibitor for NSCLC therapy.

Design, synthesis, and biological evaluation of 6-(imidazo[1,2-a] pyridin-6-yl) quinazolin-4(3H)-one derivatives as potent anticancer agents by dual targeting Aurora kinase and ROR1.

ROR1 and Aurora kinase were overexpressed in various cancers and essential for cell proliferation, survive and metastasis. Pharmaceutical inhibition of ROR1 and Aurora kinase abrogated the activation of downstream signaling and induced cancer cell apoptosis. Hence, ROR1 and Aurora kinase considered as attractive therapeutic targets for the development of anticancer drugs. In the present work, three series of novel 6-(imidazo[1,2-a] pyridin-6-yl)-quinazolin-4(3H)-one derivatives were designed and synthesized via bioisosterism and scaffold-hopping strategies guided by FLF-13, an Aurora kinase inhibitor we discovered earlier. Most of compounds in series 2 and series 3 showed submicromolar to nanomolar inhibitory activity against multiple cancer cell lines. More importantly, compounds 12d and 12f in series 3 showed nanomolar inhibitory activity against all test cancer cells. The most promising compound 12d exhibited potent inhibitory activity against Aurora A and Aurora B with IC50 values of 84.41 nM and 14.09 nM, respectively. Accordingly, compounds 12d induced G2/M phase cell cycle arrest at 24 h and polyploidy at 48 h. It's worth noting that 12d also displayed inhibitory activity against ROR1 and induce cell apoptosis. Furthermore, 12d could significantly inhibit the tumor growth in SH-SY5Y xenograft model with tumor growth inhibitory rate (IR) up to 46.31 % at 10 mg/kg and 52.66 % at 20 mg/kg. Overall, our data suggested that 12d might serve as a promising candidate for the development of therapeutic agents for cancers with aberrant expression of ROR1 and Aurora kinases by simultaneously targeting ROR1 and Aurora kinase.

Higher family and individual resilience and lower perceived stress alleviate psychological distress in female breast cancer survivors with fertility intention: a cross-sectional study.

PURPOSE: The aim of this study was to explore how family resilience and individual resilience reduce perceived stress and psychological distress in young female breast cancer survivors with fertility intention. METHODS: From June 2020 to June 2021, female breast cancer survivors were selected from the cancer centers of 10 tertiary Level A general hospitals in five cities of Sichuan Province. The survivors completed the Chinese versions of the Family Resilience Assessment Scale, Connor-Davidson Resilience Scale, Perceived Stress Scale, and a self-report distress thermometer. A multiple mediation effects test and structural equation modeling were used to explore the relationships among family resilience, individual resilience, perceived stress, and psychological distress. RESULTS: The direct effect of family resilience on perceived stress was ß = -0.320 (95% confidence interval -0.365, -0.271, P < 0.01). The direct effect of family resilience on psychological distress was ß = -0.263 (95% confidence interval -0.363, -0.153, P < 0.001). The direct effect of family resilience on individual resilience was ß = 0.593 (95% confidence interval 0.542-0.640, P < 0.001). The indirect effect of family resilience on psychological distress was ß = -0.322 (95% confidence interval -0.373, -0.274, P < 0.001). Both perceived stress and individual resilience mediated the relationship between family resilience and psychological distress. Furthermore, a partial mediating effect of perceived stress and individual resilience on family resilience and psychological distress was observed. CONCLUSION: Young female breast cancer survivors in China experience moderate levels of psychological distress.

Hardness and superconductivity in tetragonal LiB4 and NaB4.

Boron-based compounds have triggered substantial attention due to their multifunctional properties, incorporating excellent hardness and superconductivity. While tetragonal metal borides LiB4 and NaB4 with BaAl4-type structure and striking clathrate boron motif have been induced under compression, there is still a lack of deep understanding of their potential properties at ambient pressure. We herein conduct a comprehensive study on I4/mmm-structured LiB4 and NaB4 under ambient pressure via first-principles calculations. Remarkably, both LiB4 and NaB4 are found to possess high Vickers hardness of 39 GPa, which is ascribed to the robust boron framework with strong covalency. Furthermore, their high hardness values together with distinguished stability make them highly potential superhard materials. Meanwhile, electron-phonon coupling analysis reveals that both LiB4 and NaB4 are conventional phonon-mediated superconductors, with critical temperatures of 6 and 8 K at 1 atmosphere pressure (atm), respectively, mainly arising from the coupling of B 2p electronic states and the low-frequency phonon modes associated with Li-, Na-, and B-derived vibrations. This work provides valuable insights into the mechanical and superconducting behaviors of metal borides and will boost further studies of emergent borides with multiple functionalities.

Psychometric validation of the Chinese version of the Shirom-Melamed Burnout Questionnaire among parents of children with cancer.

PURPOSE: Although burnout recently emerged as a harmful syndrome in parents, no instrument has been validated to suitably assess burnout among parents of children with cancer in China. In this study, we aimed to psychometrically validate the Shirom-Melamed Burnout Questionnaire (SMBQ) among Chinese parents of children with cancer. DESIGN AND METHODS: We conducted a cross-sectional survey of 380 parents of children with cancer to psychometrically validate the SMBQ. Content validity, construct validity, convergent validity, discriminant validity, criterion-related validity, diagnosis accuracy, internal consistency, and test-retest reliability were evaluated. RESULTS: The Chinese version of the SMBQ demonstrated adequate internal consistency, good test-retest reliability, good content validity, excellent convergent and discriminant validity, and appropriate criterion-related validity. Using the parental burnout assessment as a reference criterion, the area under the curve was 0.903. The optimal cut-off point for the SMBQ was 4.833. The factor model of the SMBQ used in Chinese parents of children with cancer had a good fit. The survey revealed that Chinese parents of children with cancer experienced a high level of burnout (3.86 ± 1.03). CONCLUSIONS: The Chinese version of SMBQ was reliable and valid for assessing burnout in parents of children with cancer. Parents of children with cancer experienced a high level of burnout in China. IMPLICATIONS FOR PRACTICE: This SMBQ can be used in Chinese clinical and research settings to investigate burnout in parents who have children with cancer. Further research could examine the predictive validity and validity.

Cytostatic Activity of Sanguinarine and a Cyanide Derivative in Human Erythroleukemia Cells Is Mediated by Suppression of c-MET/MAPK Signaling.

Sanguinarine (1) is a natural product with significant pharmacological effects. However, the application of sanguinarine has been limited due to its toxic side effects and a lack of clarity regarding its molecular mechanisms. To reduce the toxic side effects of sanguinarine, its cyanide derivative (1a) was first designed and synthesized in our previous research. In this study, we confirmed that 1a presents lower toxicity than sanguinarine but shows comparable anti-leukemia activity. Further biological studies using RNA-seq, lentiviral transfection, Western blotting, and flow cytometry analysis first revealed that both compounds 1 and 1a inhibited the proliferation and induced the apoptosis of leukemic cells by regulating the transcription of c-MET and then suppressing downstream pathways, including the MAPK, PI3K/AKT and JAK/STAT pathways. Collectively, the data indicate that 1a, as a potential anti-leukemia lead compound regulating c-MET transcription, exhibits better safety than 1 while maintaining cytostatic activity through the same mechanism as 1.

Design, Synthesis and Biological Evaluation of 6-(Imidazo[1,2-a]pyridin-6-yl)quinazoline Derivatives as Anticancer Agents via PI3Kα Inhibition.

Aberrant expression of the phosphatidylinositol 3-kinase (PI3K) signalling pathway is often associated with tumourigenesis, progression and poor prognosis. Hence, PI3K inhibitors have attracted significant interest for the treatment of cancer. In this study, a series of new 6-(imidazo[1,2-a]pyridin-6-yl)quinazoline derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectra analyses. In the in vitro anticancer assay, most of the synthetic compounds showed submicromolar inhibitory activity against various tumour cell lines, among which 13k is the most potent compound with IC50 values ranging from 0.09 µΜ to 0.43 µΜ against all the tested cell lines. Moreover, 13k induced cell cycle arrest at G2/M phase and cell apoptosis of HCC827 cells by inhibition of PI3Kα with an IC50 value of 1.94 nM. These results suggested that compound 13k might serve as a lead compound for the development of PI3Kα inhibitor.

Differential attitudes and outcomes of endodontics education between mainland and non-mainland chinese students during COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has changed the learning style and campus life of dental students. This study aimed to evaluate the learning attitudes and outcomes of endodontics among mainland Chinese students and non-mainland Chinese students (students from Hong Kong, Macao, and Taiwan) during the pandemic. METHODS: A cross-sectional survey was conducted in November 2022 at the School of Stomatology, Jinan University, utilizing a self-report online questionnaire, including demographic characteristics and attitudes toward the endodontic course and the COVID-19 pandemic. The endodontics scores were collected from recruited students for further analysis. The collected data were analyzed using SPSS 22.0 software, with independent two-sample t-tests to compare continuous variables and chi-square tests for categorical variables. RESULTS: A total of 215 dental students completed the survey, with 126 (58.6%) of them being non-mainland Chinese students. Compared to mainland Chinese students, non-mainland Chinese students had lower scores in both theoretical (63.6 ± 13.5 vs. 83.2 ± 8.00) and skill (88.4 ± 5.38 vs. 90.0 ± 4.91) endodontic assessments. Non-mainland Chinese students reported significantly greater impacts of the COVID-19 pandemic on their learning emotions, personal hygiene, and future career choices compared to mainland Chinese students. CONCLUSIONS: Non-mainland Chinese students had poorer academic performance in endodontics and experienced a greater impact from the COVID-19 pandemic in terms of their studies and lives. Dental educators should consider the diversity of students and take necessary measures to support their mental health and enhance learning outcomes in the post-COVID-19 era.

Sclerostin is a promising therapeutic target for oral inflammation and regenerative dentistry.

Sclerostin is the protein product of the SOST gene and is known for its inhibitory effects on bone formation. The monoclonal antibody against sclerostin has been approved as a novel treatment method for osteoporosis. Oral health is one of the essential aspects of general human health. Hereditary bone dysplasia syndrome caused by sclerostin deficiency is often accompanied by some dental malformations, inspiring the therapeutic exploration of sclerostin in the oral and dental fields. Recent studies have found that sclerostin is expressed in several functional cell types in oral tissues, and the expression level of sclerostin is altered in pathological conditions. Sclerostin not only exerts similar negative outcomes on the formation of alveolar bone and bone-like tissues, including dentin and cementum, but also participates in the development of oral inflammatory diseases such as periodontitis, pulpitis, and peri-implantitis. This review aims to highlight related research progress of sclerostin in oral cavity, propose necessary further research in this field, and discuss its potential as a therapeutic target for dental indications and regenerative dentistry.

The potential role of circulating exosomes in protecting myocardial injury in acute myocardial infarction via regulating miR-190a-3p/CXCR4/CXCL12 pathway.

Exosomes of different origins have been found to be protective against ischemic-induced myocardial injury. This study examined the protective effects of circulating exosomes in the mice model of acute myocardial infarction (AMI) and explored the underlying molecular mechanisms. The effects of exosomes on myocardial injury were assessed in the AMI mice model. The in vivo studies showed that circulating exosomes reduced the infarcted size, improved the morphology of heart tissues and also reduced apoptosis of the heart tissues. In addition, the model mice showed an increase in the CD34 + /VEGFR2 + cell population and CD31, CXCR4 and CXCL12 expression after exosomes treatment. MiR-190a-3p was significantly down-regulated in the exosomes derived from the culture medium of hypoxia-treated human cardiomyocytes (HCMs). Further analysis revealed that miR-190a-3p could physically interact with CXCR4/CXCL12 by targeting the respective 3'UTRs. These exosomes could up-regulated CXCR4 and CXCL12 expression in the EPCs; in addition, miR-190a-3p mimics repressed CXCR4/CXCL12 expression in EPCs, while its inhibitor had opposite effects. The in vitro functional assays showed that miR-190a-3p overexpression suppressed the cell viability, proliferation, migration, adhesion and tube formation of EPCs; while miR-190a-3p inhibitor had the opposite effects; exosomes derived from the culture medium of hypoxia-treated HCMs exhibited similar actions of miR-190a-3p inhibitor. Moreover, miR-190a-3p was down-regulated in exosomes from serum in the AMI group when compared to that from sham group. Treatment with exosomes from serum in the AMI group promoted cell proliferation, migration, adhesion and tube formation of EPCs when compared to that in the sham group. More importantly, IT1t attenuated the enhanced effects of miR-190a-3p inhibition on EPC proliferation, migration, adhesion and tube formation. In conclusion, circulating exosomes exerted protective effects on myocardial injury in the AMI mice model, and down-regulation of miR-190a-3p in the circulating exosomes may exert protective effects against myocardial injury. Hypoxia induced the downregulation of miR-190a-3p in the culture medium of HCMs, and the mechanistic investigations indicated that exosomes of hypoxia-conditioned HCM culture medium promoted the cell viability, proliferation, migration, adhesion and tube formation of EPCs via regulating miR-190a-3p/CXCR4/CXCL12 pathway.

Antitumor Activity of the Zinc Oxide Nanoparticles Coated with Low-Molecular-Weight Heparin and Doxorubicin Complex In Vitro and In Vivo.

Various metal oxide nanomaterials have been widely used as carriers to prepare pH-sensitive nanomedicines to respond to the acidic tumor microenvironment promoting antitumor efficiency. Herein, we used zinc oxide nanoparticles (ZnO NPs) as metal oxide nanomaterial coated with low-molecular-weight heparin (LMHP) and doxorubicin (DOX) complex (LMHP-DOX) to prepare ZnO-LD NPs for controllable pH-triggered DOX release on the targeted site. Our results indicated that the released DOX from ZnO-LD NPs was pH-sensitive. The oxygen produced by ZnO-LD NPs in H2O2 solution was observed in in vitro experiment. The ZnO-LD NPs entered into both PC-3M and 4T1 tumor cells via clathrin-mediated endocytosis and micropinocytosis pathway. The intracellular reactive oxygen species (ROS) generated by ZnO-LD NPs could significantly increase the caspase 3/7 level, leading to tumor cell apoptosis. The in vitro and in vivo antitumor activity was confirmed in PC-3M and 4T1 cell lines or tumor-bearing mice models. The in vivo and in vitro tumor images via second-order nonlinearity of ZnO-LD NPs indicated that ZnO-LD NPs could penetrate deep into the tumor tissues. Therefore, the ZnO-LD NPs developed in our study could provide an efficient approach for the preparation of pH-sensitive nano delivery systems suitable for tumor therapy and imaging.

Three-phasic pattern of C-peptide decline in type 1 diabetes patients with partial remission.

AIMS: To explore the different patterns of C-peptide decline in patients with and without partial remission of newly diagnosed type 1 diabetes (T1D). MATERIALS AND METHODS: A total of 298 patients with new-onset T1D were followed up regularly at 3 months' interval to investigate the loss of C-peptide. Partial remission was determined by postprandial C-peptide ≥300 pmol/L or insulin dose-adjusted A1c ≤ 9 in the absence of C-peptide. Beta-cell function was defined as preserved, residual or failed by postprandial C-peptide of ≥200 pmol/L, 50-200 pmol/L or ≤50 pmol/L, respectively. RESULTS: Altogether, 199 out of 298 patients (125 adults) had partial remission. The pattern of C-peptide change in patients with partial remission was three-phasic, demonstrating an upward trend followed by a downward trend of fast first and then slow, while the pattern in patients without partial remission was biphasic, showing an initial fast fall and a subsequent slower decrease. The patterns remained consistent when patients were stratified by the age of onset. At 3 years, there were 71% of the patients with partial remission still had preserved or residual beta-cell function, while 89% of the patients who had no partial remission developed beta-cell function failure. In patients whose partial remission ended, the average C-peptide was still higher than duration-matched patients without partial remission. CONCLUSIONS: Patients with partial remission of T1D have a distinct three-phasic pattern of C-peptide decline, other than the widely recognized biphasic pattern. The effect of partial remission still exist​s after remission ends.