Aspirin-Loaded Anti-Inflammatory ZnO-SiO2 Aerogel Scaffolds for Bone Regeneration.

The increasing aging of the population has elevated bone defects to a significant threat to human life and health. Aerogel, a biomimetic material similar to an extracellular matrix (ECM), is considered an effective material for the treatment of bone defects. However, most aerogel scaffolds suffer from immune rejection and poor anti-inflammatory properties and are not well suited for human bone growth. In this study, we used electrospinning to prepare flexible ZnO-SiO2 nanofibers with different zinc concentrations and further assembled them into three-dimensional composite aerogel scaffolds. The prepared scaffolds exhibited an ordered pore structure, and chitosan (CS) was utilized as a cross-linking agent with aspirin (ASA). Interestingly, the 1%ZnO-SiO2/CS@ASA scaffolds not only exhibited good biocompatibility, bioactivity, anti-inflammation, and better mechanical properties but also significantly promoted vascularization and osteoblast differentiation in vitro. In the mouse cranial defect model, the BV/TV data showed a higher osteogenesis rate in the 1%ZnO-SiO2/CS group (10.94 ± 0.68%) and the 1%ZnO-SiO2/CS@ASA group (22.76 ± 1.83%), compared with the control group (5.59 ± 2.08%), and in vivo studies confirmed the ability of 1%ZnO-SiO2/CS@ASA to promote in situ regeneration of new bone. This may be attributed to the fact that Si4+, Zn2+, and ASA released from 1%ZnO-SiO2/CS@ASA scaffolds can promote angiogenesis and bone formation by stimulating the interaction between endothelial cells (ECs) and BMSCs, as well as inducing macrophage differentiation to the M2 type and downregulating the expression of pro-inflammatory factor (TNF-α) to modulate local inflammatory response. These exciting results and evidence suggest that it provides a new and effective strategy for the treatment of bone defects.

Yap controls notochord formation and neural tube patterning by integrating mechanotransduction with FoxA2 and Shh expression.

Correct notochord and neural tube (NT) formation is crucial to the development of the central nervous system and midline structures. Integrated biochemical and biophysical signaling controls embryonic growth and patterning; however, the underlying mechanisms remain poorly understood. Here, we took the opportunities of marked morphological changes during notochord and NT formation and identified both necessary and sufficient roles of Yap, a key mechanosensor and mechanotransducer, in biochemical signaling activation during formation of notochord and floor plate, the ventral signaling centers that pattern the dorsal-ventral axis of NT and the surrounding tissues. We showed that Yap activation by a gradient of mechanical stress and tissue stiffness in the notochord and ventral NT induces FoxA2 and Shh expression. Hedgehog signaling activation rescued NT patterning defects caused by Yap deficiency, but not notochord formation. Therefore, mechanotransduction via Yap activation acts in feedforward mechanisms to induce FoxA2 expression for notochord formation and activate Shh expression for floor plate induction by synergistically interacting with FoxA2.

A self-amplifying loop of YAP and SHH drives formation and expansion of heterotopic ossification.

Heterotopic ossification (HO) occurs as a common complication after injury or in genetic disorders. The mechanisms underlying HO remain incompletely understood, and there are no approved prophylactic or secondary treatments available. Here, we identify a self-amplifying, self-propagating loop of Yes-associated protein (YAP)-Sonic hedgehog (SHH) as a core molecular mechanism underlying diverse forms of HO. In mouse models of progressive osseous heteroplasia (POH), a disease caused by null mutations in GNAS, we found that Gnas-/- mesenchymal cells secreted SHH, which induced osteoblast differentiation of the surrounding wild-type cells. We further showed that loss of Gnas led to activation of YAP transcription activity, which directly drove Shh expression. Secreted SHH further induced YAP activation, Shh expression, and osteoblast differentiation in surrounding wild-type cells. This self-propagating positive feedback loop was both necessary and sufficient for HO expansion and could act independently of Gnas in fibrodysplasia ossificans progressiva (FOP), another genetic HO, and nonhereditary HO mouse models. Genetic or pharmacological inhibition of YAP or SHH abolished HO in POH and FOP and acquired HO mouse models without affecting normal bone homeostasis, providing a previously unrecognized therapeutic rationale to prevent, reduce, and shrink HO.

Predicted Disease-Specific Immune Infiltration Patterns Decode the Potential Mechanisms of Long Non-Coding RNAs in Primary Sjogren's Syndrome.

Primary Sjogren's syndrome (pSS) is a chronic progressive autoimmune disease with clinical phenotypic "Sicca symptoms". In some cases, the diagnosis of pSS is delayed by 6-7 years due to the inefficient differential diagnosis of pSS and non-SS "Sicca". This study aimed to investigate the difference between these two diseases, and in particular, their immunopathogenesis. Based on their gene expression profiles, we systematically defined for the first time the predicted disease-specific immune infiltration pattern of patients with pSS differentiated from normal donors and patients with non-SS "Sicca". We found that it was characterized by the aberrant abundance and interaction of tissue-infiltrated immune cells, such as a notable shift in the subpopulation of six immune cells and the perturbed abundance of nine subpopulations, such as CD4+ memory, CD8+ T-cells and gamma delta T-cells. In addition, we identified essential genes, particularly long non-coding RNAs (lncRNAs), as the potential mechanisms linked to this predicted pattern reprogramming. Fourteen lncRNAs were identified as the potential regulators associated with the pSS-specific immune infiltration pattern in a synergistic manner, among which the CTA-250D10.23 lncRNA was highly relevant to chemokine signaling pathways. In conclusion, aberrant predicted disease-specific immune infiltration patterns and relevant genes revealed the immunopathogenesis of pSS and provided some clues for the immunotherapy by targeting specific immune cells and genes.

The efficacy of analgesics in controlling orthodontic pain: a systematic review and meta-analysis.

BACKGROUND: Patients who had gone through orthodontic treatment experienced pain and discomfort which could be the highest-ranking reason for treatment disturbance or early termination. Thus, this review aimed to assess the efficacy of analgesics on the relief of pain in orthodontic treatment. METHODS: A computerized literature search was conducted in the databases of EMBASE (via OVID, 1974 to 2019 Week 50), MEDLINE (via OVID, 1946 to Dec 2019), the Cochrane Central Register of Controlled Trials (CENTRAL) (December 2019). The Cochrane Collaboration's Review Manager 5.3 software was applied in the present study. And methodological quality was evaluated by the Cochrane Risk of Bias Tool. RESULTS: We identified twelve publications including 587 patients in 19 randomized controlled trials. The results showed that the mean difference of naproxen in visual analogue scale (VAS) were - 1.45 (95% CI -2.72, - 0.19; P = .02), - 2.11 (95% CI -3.96, - 0.26; P = .03) and - 1.90 (95% CI -3.33, - 0.47; P = .009) in 2 h, 6 h and 24 h respectively. As for ibuprofen, the standard mean differences were - 1.10 (95% CI -1.49, - 0.71), - 1.63(95% CI -2.32, - 0.95) and - 1.34 (95% CI -2.12, - 0.55) at 2 h, 6 h, and 24 h, with the overall P values all < 0.001. The mean difference of acetaminophen is - 0.68, - 1.34, - 1.91 at three time points and the overall P values all < 0.01. CONCLUSIONS: This meta-analysis suggests that the use of analgesics is effective for patients in controlling orthodontic pain. Ibuprofen and naproxen are both of stable analgesic effects which could peak at 6 h, while the analgesic effect of acetaminophen increases steadily from 2 h through 24 h. Compared with ibuprofen and acetaminophen, naproxen shows a stronger analgesic effect either at 2 h or 6 h, and its effect lasts to 24 h.

Comprehensive analysis of the expression and prognosis for TFAP2 in human lung carcinoma.

BACKGROUND: The TFAP2 family of transcription factors, regulating gene expression related to vertebrate evolution, have been studied extensively in human cancer. However, the distinct roles of each TFAP2 in the expression and prognostic significance of lung carcinoma have not been elucidated yet. OBJECTIVE: This study is aimed to identify the mRNA expression and prognostic value of TFAP2 family in human lung cancer. METHODS: The transcriptional and survival data of TFAP2s in patients with lung cancer were obtained via ONCOMINE, LinkedOmics, GEPIA, cBioPortal, Kaplan-Meier Plotter and Human Protein Atlas databases. RESULTS: The results showed that expression levels of TFAP2A and TFAP2C were higher in lung adenocarcinoma and squamous cell carcinoma tissues than in normal lung tissues, whereas no difference was found in the TFAP2B expression level. TFAP2A was related to an unfavorable overall survival in lung cancer and its upregulation was significantly related to the overall survival in patients with smoking, non-chemotherapy and non-radiotherapy. CONCLUSION: This study implied that TFAP2A was a reliable prognostic factor, which could be a potential marker for improving survival and prognostic accuracy of lung cancer patients.

Efficacy and safety of pilocarpine for radiation-induced xerostomia in patients with head and neck cancer: A systematic review and meta-analysis.

BACKGROUND: Pilocarpine has been used widely in the treatment of dry mouth and glaucoma. In this review, the authors assessed the efficacy and safety of pilocarpine for patients with head and neck cancer who have radiation-induced xerostomia. TYPES OF STUDIES REVIEWED: The authors conducted a systematic search including meta-analyses and randomized controlled trials in the following databases: MEDLINE, Embase, Cochrane Library, and Science Citation Index Expanded. The primary outcome was the severity of xerostomia (measured using visual analog scale [VAS] scores). Adverse events were other outcomes of interest. The authors performed meta-analyses where appropriate. The authors used the Cochrane Collaboration's tool for assessing risk of bias to assess the quality of the study. RESULTS: The authors identified 6 studies (including 752 patients in total). The results of a meta-analysis of 3 articles showed that pilocarpine was associated with a 12-point increase in VAS score (mean difference, 12.00; 95% confidence interval [CI], 1.93-22.08; P = .02) and higher rates of adverse events compared with placebo in terms of sweating (odds ratio [OR], 3.71; 95% CI, 2.34-5.86; P < .00001). There were no differences in rhinitis (OR, 1.21; 95% CI, 0.68-2.16; P = .52) and nausea (OR, 1.44; 95% CI, 0.83-2.49; P = .19). CONCLUSIONS AND PRACTICAL IMPLICATIONS: On the basis of the best available evidence, the results of this meta-analysis provide evidence that pilocarpine offers statistically significant clinical benefits for the symptomatic treatment of radiation-induced xerostomia in patients with head and neck cancer. However, the authors of this systematic review found the best available evidence in the meta-analysis in 3 studies, 1 of which showed no effect. The authors of this systematic review suggest that these patients take 5 milligrams of pilocarpine 3 times daily, and that there is need for further study.