ß-Receptor blocker enhances the anabolic effect of PTH after osteoporotic fracture.

The autonomic nervous system plays a crucial role in regulating bone metabolism, with sympathetic activation stimulating bone resorption and inhibiting bone formation. We found that fractures lead to increased sympathetic tone, enhanced osteoclast resorption, decreased osteoblast formation, and thus hastened systemic bone loss in ovariectomized (OVX) mice. However, the combined administration of parathyroid hormone (PTH) and the ß-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice. The effect of this treatment is superior to that of treatment with PTH or propranolol alone. In vitro, the sympathetic neurotransmitter norepinephrine (NE) suppressed PTH-induced osteoblast differentiation and mineralization, which was rescued by propranolol. Moreover, NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation, whereas these effects were reversed by propranolol. Furthermore, PTH increased the expression of the circadian clock gene Bmal1, which was inhibited by NE-ßAR signaling. Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTH-stimulated osteoblast differentiation. Taken together, these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

circSNTB2 and CUL4A Induces Dysfunction of Nucleus Pulposus Cells by Competitively Binding miR-665.

Circular RNA (circRNA) plays important roles in lumbar degenerative diseases. This study aimed to investigate the role of circSNTB2 in regulating the development of lumbar disc herniation (LDH) in vitro and in vivo. The abnormally expressed circSNTB2 in intervertebral disc degeneration (IDD) through bioinformatics analysis was identified, and verified in nucleus pulposus (NP) tissues of patients with LDH. NP cells were treated with TNF-α to mimic the LDH microenvironment. RT-qPCR was applied to determine levels of mRNA and microRNA (miRNA) in clinical samples and cells. We performed CCK-8, EdU, TUNEL and flow cytometric apoptosis assays to evaluate the proliferation and apoptosis of NP cells. The predicted the miRNAs and downstream target genes were verified with the help of luciferase reporter gene and RNA pull-down experiments. Finally, we established an LDH rat model to further verify the role of circSNTB2 in vivo. circSNTB2 was significantly up-regulated in the NP tissues of LDH group and TNF-α -treated NP cells. miR-665 binds to circSNTB2 and cullin 4A (CUL4A) is the downstream target gene of miR-665. Knockdown of circSNTB2 promoted NP cells proliferation and inhibited apoptosis, which was reversed by down-regulation of miR-665. In addition, up-regulated CUL4A reversed the effects of over-expressed miR-665 on proliferation and apoptosis of NP cells. Meanwhile, results of in vivo experiments demonstrated that knocking down circSNTB2 alleviated LDH-induced thermo-mechanical pain and NP injury. In summary, circSNTB2 regulates the proliferation and apoptosis of NP by mediating miR-665 regulation of CUL4A, which provides a reliable idea for targeted therapy of LDH.

Corrigendum: Nitazoxanide, an antiprotozoal drug, reduces bone loss in ovariectomized mice by inhibition of RANKL-induced osteoclastogenesis.

[This corrects the article DOI: 10.3389/fphar.2021.781640.].

A bibliometric and visualization study of Meniere's disease: Current status and global hotspots and emerging trends.

BACKGROUND: Meniere's disease (MD) is a clinical condition characterized by endolymphatic hydrops. Persistent symptoms negatively affect patients mood, and the underlying etiology remains unclear. It is necessary to comprehensively understand the relevant publications, review the history and current status of research, and analyze hotspots and frontiers of research on MD. METHODS: We retrieved literature on Meniere's disease from 2003 to 2022 from the Web of Science database and extracted the data. Data visualization and analysis was conducted using Cite Space, VOS viewer, an online web tool, and Microsoft Office Power Point 2019. RESULTS: In total, 2847 publications were analyzed. The number of annual publications was relatively stable, with an accelerated upward trend over the past 5 years. The country with the most publications was USA (751, 26.38%), while the University of Munich contributed more publications than any other institution (117, 4.11%). The article titled "Diagnostic criteria for Meniere's disease" by Lopez-Escamez J et al in 2015 was the most cited and co-cited publication, and also had the top co-cited references with the strongest citation bursts. Naganawa S was the author with the most publications (85, 2.99%). The top 3 journals and co-cited journals were Otology Neurotology, Acta Oto Laryngologica, and Laryngoscope. Recently, the key theme words were "sensorineural hearing loss," "therapy," "intratympanic injection method," "vestibular-evoked myogenic potentials," "vestibular migraine," "magnetic resonance imaging," and "meniere's disease." CONCLUSIONS: The US has the largest number of publications and research institutions, many European countries have high-quality journals, and Japan has the highest number of scholars. The international opinion on Meniere's disease is relatively uniform. The stepped-therapy for MD is scientific and clear. Intratympanic injection of steroids and intratympanic injection of gentamicin are commonly used, but steroids are considered safer. Saccular dysfunction may be more common in patients with MD than in those with utricular dysfunctions. It is worth paying attention to study the relationship between MD and vestibular migraine through headache. Progress in magnetic resonance imaging technology is still required for the imaging diagnosis of MD.

Inhibitors and facilitators to the utilization of postpartum care in China: an integrative review.

BACKGROUND: Postpartum care is an expanding concept in China, and it is gaining vast attention in Chinese society. However, due to some Chinese traditions and rituals during the postpartum period, the utilization of modern postpartum care should be improved on both individual and community levels from different aspects. This integrative review outlined the inhibitors and facilitators of postpartum care utilization in China. METHODS: Writing an integrative review, a literature search was conducted in Chinese and English databases including Wan Fang, China National Knowledge infrastructure, Medline, Web of Science, and Embase till 31 October 2021 to capture citations covering 'postpartum care', 'utilization' and 'China'. Titles and abstracts were screened independently by three reviewers. Included studies were critically appraised using tools and checklists independently for both qualitative and quantitative studies by two different reviewers who also performed thematic synthesis. RESULTS: Of the 4359 citations screened, 41 studies (450,788 patients) were selected. Categorization of the factors influencing postpartum care utilization revealed five components: sociocultural (25 studies); educational (24 studies); organizational (12 studies); economic (19 studies); and physical (6 studies). Factors influencing postpartum care utilization both on individual and community levels were identified. They included facilitated factors such as higher mother's and partner's education level, higher socioeconomic status, lower parity, better insurance coverage, urban geographical location, Han ethnicity, and better transportation. Inhibitory factors such as under-managed policy regulation, migrants without domicile, and lower quality of care were also reported. CONCLUSION: This review has identified the inhibitors and facilitators of postpartum care utilization in China. Five major aspects including sociocultural, educational, organizational, economic, and physical components have been analysed. Results can be used to improve the utilization of modern postpartum care on both individual and community levels in Chinese society.

Simplicial epidemic model with birth and death.

In this paper, we propose a simplicial susceptible-infected-susceptible (SIS) epidemic model with birth and death to describe epidemic spreading based on group interactions, accompanying with birth and death. The site-based evolutions are formulated by the quenched mean-field probability equations for each site, which is a high-dimensional differential system. To facilitate a theoretical analysis of the influence of system parameters on dynamics, we adopt the mean-field method for our model to reduce the dimension. As a consequence, it suggests that birth and death rates influence the existence and stability of equilibria, as well as the appearance of a bistable state (the coexistence of the stable disease-free and endemic states), which is then confirmed by extensive simulations on empirical and synthetic networks. Furthermore, we find that another type of the bistable state in which a stable periodic outbreak state coexists with a steady disease-free state also emerges when birth and death rates and other parameters satisfy the certain conditions. Finally, we illustrate how the birth and death rates shift the density of infected nodes in the stationary state and the outbreak threshold, which is also verified by sensitivity analysis for the proposed model.

The feasibility of SHIMP for judging subjective vertigo and recovery in patients with vestibular neuritis.

PURPOSE: We aimed to study the results of the head impulse paradigm (HIMP) and the suppression head impulse paradigm (SHIMP) in patients with acute vestibular neuritis (AVN) to compare dizziness handicap inventory (DHI) scores before and after treatment. We also wanted to investigate the correlation between the HIMP, SHIMP and DHI score and to analyze the factors that affect the recovery with AVN in the short term. METHODS: The HIMP, SHIMP, and DHI score were assessed in 20 patients with AVN before (T0) and after treatment (T1). We collected the following indicators: T0, T1-HIMP VOR gain; T0, T1-SHIMP VOR gain; the percentage of the anti-compensatory saccades of T0-SHIMP and T1-SHIMP on the affected side; T0-DHI score, T1-DHI score; and efficacy index (EI). The correlation between HIMP and SHIMP parameters with the DHI score and EI was analyzed, and the factors that affect the recovery of patients with AVN were assessed. RESULTS: T0-SHIMP anti-compensatory saccades (%),T1-SHIMP VOR gain, and T1-SHIMP anti-compensatory saccades (%) were significantly correlated with the corresponding DHI score and EI (P < 0.05). T0, T1-HIMP VOR gain and T0-SHIMP VOR gain had no correlation with the corresponding DHI score and EI (P > 0.05). T0-SHIMP anti-compensatory saccades (%) significantly affect EI (P < 0.05). CONCLUSION: Both HIMP and SHIMP can assess the current vestibular function and recovery of AVN patients, but SHIMP can more accurately reflect the degree of subjective vertigo. At the same time, T0-SHIMP anti-compensatory saccades (%) can be used as a good index to evaluate the short-term recovery of AVN patients.

Nitazoxanide, an Antiprotozoal Drug, Reduces Bone Loss in Ovariectomized Mice by Inhibition of RANKL-Induced Osteoclastogenesis.

Nitazoxanide (NTZ) is an FDA-approved anti-parasitic drug with broad-spectrum anti-infective, anti-inflammatory, and antineoplastic potential. However, its regulatory effects on osteoclastogenesis and the underlying mechanisms remain unclear. The present study found that NTZ potently inhibited osteoclast formation at the early stage of receptor activator of NF-κB ligand-induced osteoclastogenesis in a concentration-dependent manner at a non-growth inhibitory concentration. NTZ suppressed actin ring formation and decreased osteoclast marker gene expression, including TRAP, MMP9, and cathepsin K. NTZ significantly impaired the bone resorption activity of osteoclasts. In vivo, ovariectomized mice were treated with 50, 100 and 200 mg/kg/d NTZ for 3 months. NTZ (100 mg/kg/d) administration markedly reduced ovariectomy-induced bone loss by suppressing osteoclast activity. Mechanistically, osteoclastogenesis blockade elicited by NTZ resulted from inhibition of STAT3 phosphorylation, and reduction of the Ca2+ fluorescence intensity and NFATc1 expression. NTZ weakened the binding between STAT3 and the NFATc1 promoter region. Furthermore, enforced NFATc1 expression partly rescued the impaired osteoclast differentiation in NTZ-treated RAW264.7 cells. In summary, NTZ could inhibit osteoclastogenesis and bone loss through modulation of the receptor activator of NF-κB ligand-induced STAT3-NFATc1 signaling pathway, which might be a potential alternative treatment regimen against bone destruction-related diseases including osteoporosis.

Simplicial SIRS epidemic models with nonlinear incidence rates.

Mathematical epidemiology that describes the complex dynamics on social networks has become increasingly popular. However, a few methods have tackled the problem of coupling network topology with complex incidence mechanisms. Here, we propose a simplicial susceptible-infected-recovered-susceptible (SIRS) model to investigate the epidemic spreading via combining the network higher-order structure with a nonlinear incidence rate. A network-based social system is reshaped to a simplicial complex, in which the spreading or infection occurs with nonlinear reinforcement characterized by the simplex dimensions. Compared with the previous simplicial susceptible-infected-susceptible (SIS) models, the proposed SIRS model can not only capture the discontinuous transition and the bistability of a complex system but also capture the periodic phenomenon of epidemic outbreaks. More significantly, the two thresholds associated with the bistable region and the critical value of the reinforcement factor are derived. We further analyze the stability of equilibrium points of the proposed model and obtain the condition of existence of the bistable states and limit cycles. This work expands the simplicial SIS models to SIRS models and sheds light on a novel perspective of combining the higher-order structure of complex systems with nonlinear incidence rates.

Circ_HIPK3 alleviates CoCl2-induced apoptotic injury in neuronal cells by depending on the regulation of the miR-222-3p/DUSP19 axis.

Circular RNA (circRNA) homeodomain-interacting protein kinase 3 (circ_HIPK3) has recently reported as regulator in spinal cord injury (SCI). The regulatory mechanism of circ_HIPK3 in SCI was further researched in this study. Circ_HIPK3 expression was inhibited by CoCl2 in AGE1.HN cells. The CoCl2-induced cell cycle arrest, cell proliferation inhibition and apoptosis promotion were mitigated by overexpression of circ_HIPK3. Circ_HIPK3 could target miR-222-3p and circ_HIPK3 repressed the CoCl2-induced neuronal cell injury by sponging miR-222-3p. DUSP19 was a target gene of miR-222-3p and circ_HIPK3 affected the expression of DUSP19 via binding to miR-222-3p. The regulation of circ_HIPK3 in CoCl2-induced injury of AGE1.HN cells was associated with the upregulation of DUSP19. Circ_HIPK3 acted as a pathogenic inhibitor in the progression of SCI via the miR-222-3p-mediated DUSP19 upregulation.

Clinical implementation of plasma EGFR T790M testing using droplet digital PCR in TKI-resistant NSCLC patients.

BACKGROUND: Majority of non-small cell lung cancer (NSCLC) patients progressed on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) due to acquired T790M mutation. Blood sample is increasingly used in clinical setting for EGFR T790M detection and our laboratory employed the droplet digital PCR (ddPCR) methodology for testing. This study investigated the positive rate, specimen type for rebiopsy and clinical impact of blood-based EGFR T790M testing. METHODS: We retrospectively evaluated clinical samples that underwent plasma EGFR T790M testing in TTSH Molecular Diagnostic Laboratory from August 2017 to September 2019. Data on diagnosis, EGFR activating and T790M mutations, and treatment strategies were recorded. RESULTS: A total of 104 progressive NSCLC cases were included in this study. Overall, 46 patients (44.2%) were tested T790M positive, and 47.8% of these tested positive had low levels (defined as ≤3% fractional abundance and <50 copies/mL plasma), which may be missed by the conventional methods with lower sensitivity. Of these tested with low T790M abundance, 77.3% subsequently received osimertinib. Activating mutations were not detected in 42 (40.4%) cases, indicating that the tumors were not actively shedding ctDNA. Among these, 24 patients underwent repeat testing with tissue or blood specimens. Thirteen patients were subsequently tested T790M positive and 12 of them switched treatment to osimertinib. The recommendation to repeat testing with a different biopsy or after a suitable interval increased the overall positive rate to 56.7% (59/104). CONCLUSION: The use of a highly sensitive platform such as ddPCR for the detection of low abundance T790M, and the approach of repeat testing in cases with insufficient ctDNA increased the positive rate. This in turn identified more patients who are eligible for targeted therapy.

Zona incerta projection neurons and GABAergic and GLP-1 mechanisms in the nucleus accumbens are involved in the control of gastric function and food intake.

OBJECTIVE: Our aim was to explore the effect of γ-aminobutyric acid (GABA) signaling in the nucleus accumbens (NAc) on promoting gastric function and food intake through glucagon-like peptide 1 (GLP-1)-sensitive gastric distension (GD) neurons under the regulatory control of the zona incerta (ZI). METHODS: GABA neuronal projections were traced using retrograde tracing following fluorescence immunohistochemistry. An extracellular electrophysiological recording method was used to observe the firing of neurons in the NAc. HPLC was used to quantify the GABA and glutamate levels in the NAc after electrical stimulation of the ZI. Gastric functions including gastric motility and secretion, as well as food intake, were measured after the administration of different concentrations of GABA in the NAc or electrical stimulation of the ZI. RESULTS: Some of the GABA-positive neurons arising from the ZI projected to the NAc. Some GABA-A receptor (GABA-AR)-immunoreactive neurons in the NAc were also positive for GLP-1 receptor (GLP-1R) immunoreactivity. The firing of most GLP-1-sensitive GD neurons was decreased by GABA infusion in the NAc. Intra-NAc GABA administration also promoted gastric function and food intake. The responses induced by GABA were partially blocked by the GABA-AR antagonist bicuculline (BIC) and weakened by the GLP-1R antagonist exendin 9-39 (Ex9). Electrical stimulation of the ZI changed the firing patterns of most GLP-1-sensitive GD neurons in the NAc and promoted gastric function and food intake. Furthermore, these excitatory effects induced by electrical stimulation of the ZI were weakened by preadministration of BIC in the NAc. CONCLUSION: Retrograde tracing and immunohistochemical staining showed a GABAergic pathway from the ZI to the NAc. GABAergic and GLP-1 mechanisms in the NAc are involved in the control of gastric function and food intake. In addition, the interaction (direct or indirect) between the ZI and these NAc mechanisms is involved in the control of gastric function and food intake.

Efficacy of cattle encephalon glycoside and ignotin in patients with acute cerebral infarction: a randomized, double-blind, parallel-group, placebo-controlled study.

Cattle encephalon glycoside and ignotin (CEGI) injection is a compound preparation formed by a combination of muscle extract from healthy rabbits and brain gangliosides from cattle, and it is generally used as a neuroprotectant in the treatment of central and peripheral nerve injuries. However, there is still a need for high-level clinical evidence from large samples to support the use of CEGI. We therefore carried out a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in which we recruited 319 patients with acute cerebral infarction from 16 centers in China from October 2013 to May 2016. The patients were randomized at a 3:1 ratio into CEGI (n = 239; 155 male, 84 female; 61.2 ± 9.2 years old) and placebo (n = 80; 46 male, 34 female; 63.2 ± 8.28 years old) groups. All patients were given standard care once daily for 14 days, including a 200 mg aspirin enteric-coated tablet and 20 mg atorvastatin calcium, both taken orally, and intravenous infusion of 250-500 mL 0.9% sodium chloride containing 40 mg sodium tanshinone IIA sulfonate. Based on conventional treatment, patients in the CEGI and placebo groups were given 12 mL CEGI or 12 mL sterile water, respectively, in an intravenous drip of 250 mL 0.9% sodium chloride (2 mL/min) once daily for 14 days. According to baseline National Institutes of Health Stroke Scale scores, patients in the two groups were divided into mild and moderate subgroups. Based on the modified Rankin Scale results, the rate of patients with good outcomes in the CEGI group was higher than that in the placebo group, and the rate of disability in the CEGI group was lower than that in the placebo group on day 90 after treatment. In the CEGI group, neurological deficits were decreased on days 14 and 90 after treatment, as measured by the National Institutes of Health Stroke Scale and the Barthel Index. Subgroup analysis revealed that CEGI led to more significant improvements in moderate stroke patients. No drug-related adverse events occurred in the CEGI or placebo groups. In conclusion, CEGI may be a safe and effective treatment for acute cerebral infarction patients, especially for moderate stroke patients. This study was approved by the Ethical Committee of Peking University Third Hospital, China (approval No. 2013-068-2) on May 20, 2013, and registered in the Chinese Clinical Trial Registry (registration No. ChiCTR1800017937).

miR-140-3p exhibits repressive functions on preosteoblast viability and differentiation by downregulating MCF2L in osteoporosis.

Previous research manifested that miR-140-3p was a latent biomarker for osteoporosis. Nevertheless, the mechanism of miR-140-3p in osteoporosis is still not clear and needs ulteriorly studying. The purpose of our paper was to ulteriorly probe the underlying mechanism of miR-140-3p on osteoporosis. Firstly, based on the data acquired from GEO database, we found that miR-140-3p was highly expressed; meanwhile, MCF2L was lowly expressed in osteoporosis patients. Upregulation/downregulation of miR-140-3p by miR-140-3p mimic/inhibitor restrained/promoted MC3T3-E1 cell viability and differentiation. However, miR-140-3p over-expression/downregulation accelerated/repressed MC3T3-E1 cell apoptosis. MCF2L was forecasted as a target of miR-140-3p by miRanda, miRWalk, and TargetScan miRNA target gene prediction software. Luciferase reporter assay confirmed that MCF2L could be directly targeted by miR-140-3p. Moreover, we identified that the expression of MCF2L was negatively regulated by miR-140-3p. From rescue assays, we discovered that knockdown of MCF2L weakened the promoting influence of miR-140-3p ablation on MC3T3-E1 cell viability and differentiation, and receded the suppressing impact of miR-140-3p reduction on MC3T3-E1 cell apoptosis. Above all, this research disclosed that miR-140-3p repressed preosteoblast viability and differentiation while promoted preosteoblast apoptosis via targeting MCF2L. Our discoveries might afford a theoretical basis of developing a latent novel target for osteoporosis therapy.

Cervical kyphosis in asymptomatic populations: incidence, risk factors, and its relationship with health-related quality of life.

BACKGROUND: Cervical kyphosis has been pointed out in asymptomatic populations. The purposes of this study were (1) to investigate the incidence of cervical kyphosis in asymptomatic populations, (2) to identify risk factors related to cervical kyphosis, and (3) to assess the relationship between cervical kyphosis and health-related quality of life (HRQOL). METHODS: A cohort of 235 asymptomatic volunteers' records was retrospectively analyzed. Radiographic parameters of the coronal and sagittal planes were measured in the full-length spine x-ray. All patients were classified into two groups based on the cervical lordosis angle: cervical lordosis (CL) and cervical kyphosis (CK). HRQOL was evaluated by EQ-5D and SF-36 (PCS and MCS) questionnaires. RESULTS: CK was observed in 90 of 235 (38.3%) participants. There was a significant difference with regard to age between volunteers with CK and CL (32.23 ± 8.12 vs. 42.12 ± 6.14, p < 0.05). Several parameters had a significant relationship with CK, including TK, T1 slope, TIA, SVA, and CT. Logistic regression analysis identified age, TK, T1 slope, and SVA as independent risk factors of CK. In addition, there was a negative correlation between CK and the parameters of HRQOL (EQ-5D, - 0.63; PCS, - 0.68; MCS, - 0.59). CONCLUSIONS: The incidence of CK in normal populations is 38.3%. Some spinal parameters are related to CK. CK is associated with the HRQOL.

Regulation of stress-induced gastric ulcers via central oxytocin and a potential mechanism through the VTA-NAc dopamine pathway.

BACKGROUND: Oxytocin (OT) plays an important role in regulating gastric function. How OT regulates stress-induced gastric ulcers is not understood. We investigated OT's protective role in stress-induced gastric ulcers, with a focus on OT's interaction with the ventral tegmental area (VTA) to nucleus accumbens (NAc) dopamine pathway. METHODS: Drugs administration into the rats brain nuclei by brain stereotaxic apparatus, to examine related changes in gastric ulcer index, pH of gastric content, and mucus secretion, and to determine complex interactions between OT and DA systems in the regulation of stress and gastric functions. KEY RESULTS: Neurons in the VTA were co-immunoreactive for the OT receptor (OTR) and DA. In a rat model of stress-induced ulcer, water-immersion restricted stress, direct administration of OT into the VTA significantly reduced gastric ulcer index and increased the pH of gastric content and mucus secretion. OT's effects were eliminated by pretreatment with the OTR antagonist atosiban in the VTA and weakened with pretreatment of the DA D2 receptor (DA D2R) antagonist raclopride in the NAc. In OTR gene knockout (Oxtr-/- ) mice, OT's protective effect was lost. OT administered to the VTA of dorsal motor nucleus of the vagus (DMV)-lesioned rats had minimal protective effects on gastric mucosa. CONCLUSIONS AND INFERENCES: This study provides important data necessary for a deeper understanding of the complex interactions between OT and DA systems in the regulation of stress and gastric functions. It provides relevant mechanistic clues into OT's role as a protective factor against stress-induced changes to gastric function.

Mammalian Target of Rapamycin Complex 1 Signaling Is Required for the Dedifferentiation From Biliary Cell to Bipotential Progenitor Cell in Zebrafish Liver Regeneration.

The liver has a high regenerative capacity. Upon two-thirds partial hepatectomy, the hepatocytes proliferate and contribute to liver regeneration. After severe liver injury, when the proliferation of residual hepatocytes is blocked, the biliary epithelial cells (BECs) lose their morphology and express hepatoblast and endoderm markers, dedifferentiate into bipotential progenitor cells (BP-PCs), then proliferate and redifferentiate into mature hepatocytes. Little is known about the mechanisms involved in the formation of BP-PCs after extreme liver injury. Using a zebrafish liver extreme injury model, we found that mammalian target of rapamycin complex 1 (mTORC1) signaling regulated dedifferentiation of BECs and proliferation of BP-PCs. mTORC1 signaling was up-regulated in BECs during extreme hepatocyte ablation and continuously expressed in later liver regeneration. Inhibition of mTORC1 by early chemical treatment before hepatocyte ablation blocked the dedifferentiation from BECs into BP-PCs. Late mTORC1 inhibition after liver injury reduced the proliferation of BP-PC-derived hepatocytes and BECs but did not affect BP-PC redifferentiation. mTOR and raptor mutants exhibited defects in BEC transdifferentiation including dedifferentiation, BP-PC proliferation, and redifferentiation, similar to the chemical inhibition. Conclusion: mTORC1 signaling governs BEC-driven liver regeneration by regulating the dedifferentiation of BECs and the proliferation of BP-PC-derived hepatocytes and BECs.

Identification of hub genes associated with postmenopausal osteoporosis by Gibbs sampling method.

Underlying pivotal pathways were identified to reveal potential key genes correlated with postmenopausal osteoporosis (PMOP). The pathways were enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG) with genes intersection greater than 5 based on gene expression profile data, and the acquired pathways were then transformed to Markov chain (MC). Gibbs sampling was conducted to obtain a new MC. Moreover, the average probabilities of each pathway in normal and PMOP were computed via an MC Monte Carlo (MCMC) algorithm, and differential pathways were identified based on probabilities more than 0.7. In addition, frequencies of appearance of pathway genes were counted via MCMC and the hub genes were achieved with the probabilities of gene expression efficiencies in two states. Judging by the gene intersection more than 5, overall 280 pathways were determined. After Gibbs sampling, 2 differential pathways were obtained on the basis of probabilities more than 0.7. Moreover, the hub genes comprising TNNC1, MYL2, and TTN were achieved according to probabilities more than 0.7. The identified pathways and the three hub genes probably are useful for developing approaches for the diagnosis and treatment of PMOP in future preclinical and clinical applications.

Incorporating simvastatin/poloxamer 407 hydrogel into 3D-printed porous Ti6Al4V scaffolds for the promotion of angiogenesis, osseointegration and bone ingrowth.

Three-dimensional porous titanium alloys printed via electron beam melting have low stiffness similar to that of cortical bone and are promising scaffolds for orthopedic applications. However, the bio-inert nature of titanium alloy is poorly compatible with bone ingrowth. We previously observed that simvastatin/poloxamer 407 thermosensitive hydrogel induces endogenous angiogenic/osteogenic growth factors and promotes angiogenesis and osteogenesis, but the mechanical properties of this hydrogel are poor. The purpose of this study was to construct 3D-printed porous titanium scaffolds (pTi scaffolds) filled with simvastatin/hydrogel and evaluate the effects of this composite on osseointegration, bone ingrowth and neovascularization using a tibial defect rabbit model. Four and eight weeks after implantation, the bone volume, bone mineral density, mineral apposition rate, and push-in maximum force of the pTi scaffolds filled with simvastatin/hydrogel were significantly higher than those without simvastatin (p < 0.05). Moreover, filling with simvastatin/hydrogel significantly enhanced vascularization in and around the pTi scaffolds, and a significant correlation was observed between the volume of new bone and neovascularization (p < 0.01). In conclusion, incorporating simvastatin/poloxamer 407 hydrogel into pTi scaffolds significantly improves neovascularization, osseointegration and bone ingrowth.

Knockdown of UBE2T Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion by Suppressing the PI3K/Akt Signaling Pathway.

Ubiquitin-conjugating enzyme E2T (UBE2T), a member of the E2 family, was found to be overexpressed in a great many cancers such as bladder cancer, lung cancer, and prostate cancer. However, there have been no reports on the role of UBE2T in osteosarcoma. In this study, we tried to make the effects of UBE2T on osteosarcoma clear. The study results showed that UBE2T was overexpressed in osteosarcoma tissues and cell lines. Moreover, UBE2T knockdown inhibited osteosarcoma cell proliferation, migration, and invasion. We also observed that UBE2T downregulation could suppress the activity of the PI3K/Akt signaling pathway. Therefore, we concluded that UBE2T exerted its inhibitory effects on osteosarcoma cells via suppressing the PI3K/Akt signaling pathway. These findings indicated that UBE2T may be a potential therapeutic target for osteosarcoma treatment.