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Front Pharmacol ; 12: 728729, 2021.
Article En | MEDLINE | ID: mdl-34489713

Cortical neurons oscillate between Up and Down states during slow wave sleep and general anesthesia. Recent studies show that Up/Down oscillations also occur during quiet wakefulness. Arousal eliminates Down states and transforms Up/Down oscillations to a persistent Up state. Further evidence suggests that Up/Down oscillations are crucial to memory consolidation, whereas their transition to a persistent Up state is essential for arousal and attention. We have shown that D-amphetamine promotes cortical Up state, and the effect depends on activation of central α1A adrenergic receptors. Here, we report that dopamine also plays a role in D-amphetamine's effect. Thus, using local-field-potential recording in the prefrontal cortex in chloral hydrate-anesthetized rats, we showed that the Up-state promoting effect of D-amphetamine was attenuated by antagonists at either D1 or D2-like dopamine receptors. The effect was also partially mimicked by co-activation of D1 and D2-like receptors. These results are consistent with the fact that D-amphetamine increases the release of both norepinephrine and dopamine. They are also in agreement with studies showing that dopamine promotes wakefulness and mediates D-amphetamine-induced emergence from general anesthesia. The effect of D-amphetamine was not mimicked, however, by activation of either D1 or D2-like receptors alone, indicating an interdependence between D1 and D2-like receptors. The dopamine/norepinephrine precursor L-DOPA also failed to promote the Up state. While more studies are needed to understand the difference between L-DOPA and D-amphetamine, our finding may provide an explanation for why L-DOPA lacks significant psychostimulant properties and is ineffective in treating attention-deficit/hyperactivity disorder.

Int J Mol Sci ; 22(16)2021 Aug 20.
Article En | MEDLINE | ID: mdl-34445671

C-type natriuretic peptide (CNP) is an important vascular regulator that is present in the brain. Our previous study demonstrated the innate neuroprotectant role of CNP in the neonatal brain after hypoxic-ischemic (HI) insults. In this study, we further explored the role of CNP in cerebrovascular pathology using both in vivo and in vitro models. In a neonatal mouse HI brain injury model, we found that intracerebroventricular administration of recombinant CNP dose-dependently reduces brain infarct size. CNP significantly decreases brain edema and immunoglobulin G (IgG) extravasation into the brain tissue, suggesting a vasculoprotective effect of CNP. Moreover, in primary brain microvascular endothelial cells (BMECs), CNP dose-dependently protects BMEC survival and monolayer integrity against oxygen-glucose deprivation (OGD). The vasculoprotective effect of CNP is mediated by its innate receptors NPR2 and NPR3, in that inhibition of either NPR2 or NPR3 counteracts the protective effect of CNP on IgG leakage after HI insult and BMEC survival under OGD. Of importance, CNP significantly ameliorates brain atrophy and improves neurological deficits after HI insults. Altogether, the present study indicates that recombinant CNP exerts vascular protection in neonatal HI brain injury via its innate receptors, suggesting a potential therapeutic target for the treatment of neonatal HI brain injury.

Hypoxia-Ischemia, Brain/pathology , Natriuretic Peptide, C-Type/pharmacology , Vascular System Injuries/prevention & control , Animals , Animals, Newborn , Brain/metabolism , Brain Edema/pathology , Brain Infarction/metabolism , Brain Injuries/pathology , Cells, Cultured , Endothelial Cells/metabolism , Female , Hypoxia-Ischemia, Brain/metabolism , Infusions, Intraventricular , Male , Mice , Natriuretic Peptide, C-Type/metabolism , Natriuretic Peptide, C-Type/physiology , Neuroprotective Agents , Vascular System Injuries/metabolism
Phys Rev Lett ; 126(21): 211803, 2021 May 28.
Article En | MEDLINE | ID: mdl-34114849

We report constraints on light dark matter through its interactions with shell electrons in the PandaX-II liquid xenon detector with a total 46.9 tonnes/day exposure. To effectively search for these very low energy electron recoils, ionization-only signals are selected from the data. 1821 candidates are identified within an ionization signal range between 50 and 75 photoelectrons, corresponding to a mean electronic recoil energy from 0.08 to 0.15 keV. The 90% C.L. exclusion limit on the scattering cross section between the dark matter and electron is calculated with systematic uncertainties properly taken into account. Under the assumption of point interaction, we provide the world's most stringent limit within the dark matter mass range from 15 to 30 MeV/c^{2}, with the corresponding cross section from 2.5×10^{-37} to 3.1×10^{-38} cm^{2}.

J Bone Miner Metab ; 39(6): 962-973, 2021 Nov.
Article En | MEDLINE | ID: mdl-34191125

INTRODUCTION: Corticotomy is widely used in clinical practice to accelerate tooth movement and shorten the duration of orthodontic treatment. It is effective, but an invasive surgery is needed to induce alveolar bone osteopenia that enable rapid tooth movement. In this study, we discovered the potential of 6-shogaol as a more patient-friendly non-invasive alternative to induce transient osteopenia and accelerate tooth movement. MATERIALS AND METHODS: The effects of 6-shogaol on the bone marrow macrophages (BMM) proliferation and osteoclast differentiation, and bone resorption were determined in vitro. Sprague-Dawley rats were distributed into three groups: CON, IPinj or Localinj and euthanized at day 28. Micro-CT, histology, immunohistological, and TUNEL analysis were performed to evaluate the tooth movement acceleration effect of 6-shogaol. RESULTS: In vitro, 6-shogaol promotes osteoclast differentiation and functional demineralization of alveolar bone. RANKL-induced mRNA expression of osteoclastic-specific genes was significantly higher in the presence of 6-shogaol. A dose-dependent increase in the area of TRAP-positive cells was observed with 6-shogaol treatment. F-actin ring formation and increased bone resorption confirmed that osteoclasts treated with 6-shogaol were mature and functional. 6-shogaol stimulated JNK activation and NFATc1 expression during osteoclast differentiation. In vivo, 6-shogaol promotes alveolar bone transient osteopenia and accelerates orthodontic tooth movement. Alveolar bone mass was reduced, more osteoclasts were observed in bone resorption lacunae on the compression side, and the expression of RANKL and sclerostin were higher than the control group. In conclusion, our results suggest that 6-shogoal accelerates tooth movement by inducing osteopenia by a mechanism similar to surgically induced bone injury.

Bone Resorption , Tooth Movement Techniques , Animals , Catechols , Humans , NFATC Transcription Factors , Osteoclasts , Rats , Rats, Sprague-Dawley
Am J Orthod Dentofacial Orthop ; 160(1): 94-100, 2021 Jul.
Article En | MEDLINE | ID: mdl-33906775

INTRODUCTION: This study aimed to evaluate the association of esthetic expectations with self-reported personal characteristics, anxiety, depression, self-esteem, oral health-related quality of life, and the Orthognathic Quality of Life Questionnaire (OQLQ) in Chinese adult patients before orthognathic treatment. METHODS: This study involved 213 patients with clinically significant skeletal deformity requiring orthognathic surgery for comprehensive treatment. Each patient completed a series of Chinese version scales, including the self-rating anxiety scale, self-rating depression scale, self-esteem scale, the Oral Health Impact Profile-14 questionnaire, and the OQLQ. The patients' self-reported personal characteristics were also recorded, including facial appearance ratings before and after orthognathic treatment, highest education level, mean monthly income, and enthusiasm toward orthodontic or orthognathic treatment. The Least Absolute Shrinkage and Selection Operator multivariate linear regression model was conducted for the selection of the above factors. The final multivariate linear regression model was built with variables identified under the optimal tuning parameter. RESULTS: A total of 213 patients (87 men and 126 women) were included in this study. The patients' esthetic expectation scores were significantly associated with their total scores, which encompassed the education level, mean monthly income, enthusiasm toward orthodontic or orthognathic treatment, self-esteem scale, the Chinese version of the 14-item Oral Health Impact Profile questionnaire, OQLQ, etc. In the multivariate linear regression model, the OQLQ, enthusiasm toward orthognathic treatment, depression, and expected facial appearance score after the treatment were the most important factors to predict esthetic expectation. CONCLUSIONS: High esthetic expectations for orthognathic treatment were mostly associated with higher expected facial appearance scores after the treatment, greater enthusiasm toward orthognathic treatment, worse depression (confusion), and 2 domains (social aspects of deformity and oral function) of OQLQ. Therefore, OQLQ, enthusiasm toward orthognathic treatment, and expected facial appearance score after treatment may be used to predict patients' esthetic expectations before commencing orthognathic treatment in daily clinical practice.

Motivation , Orthognathic Surgical Procedures , Adult , China , Esthetics, Dental , Female , Humans , Male , Quality of Life , Surveys and Questionnaires
J Neuroinflammation ; 18(1): 6, 2021 Jan 05.
Article En | MEDLINE | ID: mdl-33402183

BACKGROUND: Neonatal hypoxic-ischemic (HI) brain injury is a leading cause of acute mortality and chronic disability in newborns. Our previous studies demonstrated that HI insult significantly increased microRNA-210 (miR-210) in the brain of rat pups and inhibition of brain endogenous miR-210 by its inhibitor (LNA) provided neuroprotective effect in HI-induced brain injury. However, the molecular mechanisms underpinning this neuroprotection remain unclear. METHODS: We made a neonatal HI brain injury model in mouse pups of postnatal day 7 to uncover the mechanism of miR-210 in targeting the ten eleven translocation (TET) methylcytosine dioxygenase 2 that is a transcriptional suppressor of pro-inflammatory cytokine genes in the neonatal brain. TET2 silencing RNA was used to evaluate the role of TET2 in the neonatal HI-induced pro-inflammatory response and brain injury. MiR-210 mimic and inhibitor (LNA) were delivered into the brain of mouse pups to study the regulation of miR-210 on the expression of TET2. Luciferase reporter gene assay was performed to validate the direct binding of miR-210 to the 3' untranslated region of the TET2 transcript. Furthermore, BV2 mouse microglia cell line was employed to confirm the role of miR-210-TET2 axis in regulating pro-inflammatory response in microglia. Post-assays included chromatin immunoprecipitation (ChIP) assay, co-immunoprecipitation, RT-PCR, brain infarct assay, and neurobehavioral test. Student's t test or one-way ANOVA was used for statistical analysis. RESULTS: HI insult significantly upregulated miR-210, downregulated TET2 protein abundance, and increased NF-κB subunit p65 acetylation level and its DNA binding capacity to the interleukin 1 beta (IL-1ß) promoter in the brain of mouse pups. Inhibition of miR-210 rescued TET2 protein level from HI insult and miR-210 mimic decreased TET2 protein level in the brain of mouse pups, suggesting that TET2 is a functional target of miR-210. The co-immunoprecipitation was performed to reveal the role of TET2 in HI-induced inflammatory response in the neonatal brain. The result showed that TET2 interacted with NF-κB subunit p65 and histone deacetylase 3 (HDAC3), a co-repressor of gene transcription. Furthermore, TET2 knockdown increased transcriptional activity of acetyl-p65 on IL-1ß gene in the neonatal brain and enhanced HI-induced upregulation of acetyl-p65 level and pro-inflammatory cytokine expression. Of importance, TET2 knockdown exacerbated brain infarct size and neurological deficits and counteracted the neuroprotective effect of miR-210 inhibition. Finally, the in vitro results demonstrated that the miR-210-TET2 axis regulated pro-inflammatory response in BV2 mouse microglia cell line. CONCLUSIONS: The miR-210-TET2 axis regulates pro-inflammatory cytokine expression in microglia, contributing to neonatal HI brain injury.

DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/biosynthesis , Down-Regulation/physiology , Hypoxia-Ischemia, Brain/metabolism , Inflammation Mediators/metabolism , MicroRNAs/biosynthesis , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/biosynthesis , Animals , Animals, Newborn , Cell Line , Female , Hypoxia-Ischemia, Brain/pathology , Male , Mice
Eur J Pharmacol ; 892: 173826, 2021 Feb 05.
Article En | MEDLINE | ID: mdl-33347825

Finding alternative treatments for attention-deficit/hyperactivity disorder (ADHD) is crucial given the safety and efficacy problems of current ADHD medications. Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS), is a norepinephrine prodrug that enhances brain norepinephrine and dopamine levels. In this study, we used electrophysiological tests to examine effects of L-DOPS on the prefrontal cortex (PFC) and dopamine neurons in the ventral tegmental area. We also conducted behavioral tests to assess L-DOPS' effects on ADHD-like behaviors in rats. In chloral hydrate-anesthetized rats, PFC local field potentials oscillated between the active, depolarized UP state and the hyperpolarized DOWN state. Mimicking the effect of d-amphetamine, L-DOPS, given after the peripheral amino acid decarboxylase inhibitor, benserazide (BZ), increased the amount of time the PFC spent in the UP state, indicating an excitatory effect of L-DOPS on PFC neurons. Like d-amphetamine, L-DOPS also inhibited dopamine neurons, an effect significantly reversed by the D2-like receptor antagonist raclopride. In the behavioral tests, BZ + L-DOPS improved hyperactivity, inattention and impulsive action of the adolescent spontaneously hypertensive rat (SHR/NCrl), well-validated animal model of the combined type of ADHD. BZ + L-DOPS also reduced impulsive choice and impulsive action of Wistar rats, but did not ameliorate the inattentiveness of Wistar Kyoto rats (WKY/NCrl), proposed model of the ADHD-predominantly inattentive type. In conclusion, L-DOPS produced effects on the PFC and dopamine neurons characteristic of drugs used to treat ADHD. BZ + L-DOPS ameliorated ADHD-like behaviors in rats suggesting its potential as an alternative ADHD treatment.

Attention Deficit Disorder with Hyperactivity/drug therapy , Behavior, Animal/drug effects , Dopamine Agents/pharmacology , Dopaminergic Neurons/drug effects , Droxidopa/pharmacology , Prefrontal Cortex/drug effects , Ventral Tegmental Area/drug effects , Animals , Attention/drug effects , Attention Deficit Disorder with Hyperactivity/metabolism , Attention Deficit Disorder with Hyperactivity/physiopathology , Attention Deficit Disorder with Hyperactivity/psychology , Benserazide/pharmacology , Delay Discounting/drug effects , Disease Models, Animal , Dopaminergic Neurons/metabolism , Drug Therapy, Combination , Locomotion/drug effects , Male , Maze Learning/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Sprague-Dawley , Species Specificity , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/physiopathology
Addict Biol ; 26(1): e12879, 2021 01.
Article En | MEDLINE | ID: mdl-32003119

Cortical neurons oscillate synchronously between the Up and Down state during slow-wave sleep and general anesthesia. Using local-field-potential recording in the rat prefrontal cortex (PFC), we have shown that systemic administration of methylphenidate promotes PFC Up states and reduces PFC slow oscillation, suggesting a depolarizing effect of the drug on PFC neurons. Here, we report that systemic injection of d-amphetamine produced similar effects. Our evidence further suggests that norepinephrine (NE) plays a major role in the effects of d-amphetamine since they were mimicked by the NE reuptake inhibitors tomoxetine and nisoxetine and completely blocked by the α1 receptor antagonist prazosin. The effects of d-amphetamine persisted, however, in the presence of α2 or ß receptor blockade. Experiments with α1 subtype-selective antagonists further suggest that d-amphetamine's effects depend on activation of central, but not peripheral, α1A receptors. Unexpectedly, the putative α1 receptor agonist cirazoline failed to mimic the effects of d-amphetamine. Previous studies suggest that cirazoline is also an antagonist at α2 receptors. Furthermore, it is a partial, not full, agonist at α1B and α1D receptors. Whether or not these properties of cirazoline contribute to its failure to mimic d-amphetamine's effects remains to be determined. Methylphenidate and d-amphetamine are two most common medications for attention-deficit/hyperactivity disorder (ADHD). Both, however, are associated with adverse effects including abuse potential and psychotomimetic effects. Further understanding of their mechanisms of action will help develop safer treatments for ADHD and offer new insights into drug addiction and psychosis.

Amphetamine/pharmacology , Prefrontal Cortex/drug effects , Receptors, Adrenergic/physiology , Animals , Atomoxetine Hydrochloride/pharmacology , Dextroamphetamine/pharmacology , Dopamine , Male , Methylphenidate/pharmacology , Neurons/drug effects , Norepinephrine/metabolism , Prazosin , Rats
J Cell Physiol ; 236(1): 664-676, 2021 01.
Article En | MEDLINE | ID: mdl-32572964

Balancing the process of bone formation and resorption is important in the maintenance of healthy bone. Therefore, the discovery of novel factors that can regulate bone metabolism remains needed. Irisin is a newly identified hormone-like peptide. Recent studies have reported the involvement of irisin in many physiological and pathological conditions with bone mineral density changes, including osteopenia and osteoporotic fractures. In this study, we generated the first line of Osx-Cre:FNDC5/irisin KO mice, in which FNDC5/irisin was specifically deleted in the osteoblast lineage. Gene and protein expressions of irisin were remarkably decreased in bones but no significant differences in other tissues were observed in knockout mice. FNDC5/irisin deficient mice showed a lower bone density and significantly delayed bone development and mineralization from early-stage to adulthood. Our phenotypical analysis exhibited decreased osteoblast-related gene expression and increased osteoclast-related gene expression in bone tissues, and reduced adipose tissue browning due to bone-born irisin deletion. By harvesting and culturing MSCs from the knockout mice, we found that osteoblastogenesis was inhibited and osteoclastogenesis was increased. By using irisin stimulated wildtype primary cells as a gain-of-function model, we further revealed the effects and mechanisms of irisin on promoting osteogenesis and inhibiting osteoclastogenesis in vitro. In addition, positive effects of exercise, including bone strength enhancement and body weight loss were remarkably weakened due to irisin deficiency. Interestingly, these changes can be rescued by supplemental administration of recombinant irisin during exercise. Our study indicates that irisin plays an important role in bone metabolism and the crosstalk between bone and adipose tissue. Irisin represents a potential molecule for the prevention and treatment of bone metabolic diseases.

Bone and Bones/metabolism , Fibronectins/genetics , Muscle, Skeletal/metabolism , Osteoblasts/metabolism , Osteogenesis/genetics , Animals , Bone Diseases, Metabolic/metabolism , Fibronectins/deficiency , Osteogenesis/drug effects , Transcription Factors/genetics , Transcription Factors/metabolism
J Craniofac Surg ; 2020 Nov 11.
Article En | MEDLINE | ID: mdl-33181618

This study aimed to design and fabricate a customized distractor based on 3D printing technology and compare its mechanical properties with conventional distractor. The investigators designed and implemented a study composed of conventional and customized distractors. The design of customized distractor was based on the specification of conventional mandibular distractors and was fabricated using selective laser melting (SLM) technology. The same type of conventional distractors served as control group. Vickers-hardness test, three-point bending test and welding strength test were carried out for the conventional and customized distractor respectively and data was analyzed with t test using SPSS13.0 software package. The sample was composed of 18 distractors grouped as follows: customized distractor (n = 9) and conventional distractor (n = 9). The customized distractor showed better result than the conventional distractor in mechanical property tests, with statistically significant differences in Vickers-hardness and maximum load (P < 0.05), and no significant differences in yield strength and welding strength (P > 0.05). The results of this study suggest indicated that compared to the conventional distractor, the customized distractor had better mechanical properties and could be used in maxillofacial distraction osteogenesis.

Front Aging Neurosci ; 12: 251, 2020.
Article En | MEDLINE | ID: mdl-32973487

Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with cognitive impairment and later dementia among the elderly. Mounting evidence shows that adverse maternal environments during the fetal development increase the risk of diseases later in life including neurological disorders, and suggests an early origin in the development of AD-related dementia (ADRD) in utero. In the present study, we investigated the impact of antenatal hypoxia and fetal stress on the initiation of AD-related pathology in offspring of 5xFAD mice. We showed that fetal hypoxia significantly reduced brain and body weight in the fetal and the early postnatal period, which recovered in young adult mice. Using spontaneous Y-maze, novel object recognition (NOR), and open field (OF) tasks, we found that antenatal hypoxia exacerbated cognitive decline in offspring of 5xFAD compared with normoxia control. Of interest, fetal hypoxia did not alter intraneuronal soluble amyloid-ß (Aß) oligomer accumulation in the cortex and hippocampus in 5xFAD mouse offspring, indicating that antenatal hypoxia increased the vulnerability of the brain to synaptotoxic Aß in the disease onset later in life. Consistent with the early occurrence of cognitive decline, we found synapse loss but not neuronal death in the cerebral cortex in 5xFAD but not wild-type (WT) offspring exposed to antenatal hypoxia. Furthermore, we also demonstrated that antenatal hypoxia significantly increased microglial number and activation, and reactive astrogliosis in the cerebral cortex in WT offspring. Moreover, antenatal hypoxia resulted in an exacerbated increase of microgliosis and astrogliosis in the early stage of AD in 5xFAD offspring. Together, our study reveals a causative link between fetal stress and the accelerated onset of AD-related pathology, and provides mechanistic insights into the developmental origin of aging-related neurodegenerative disorders.

Front Cell Dev Biol ; 8: 445, 2020.
Article En | MEDLINE | ID: mdl-32626707

The contributing factors and the origins of precursor cells in traumatic heterotopic ossification around the temporomandibular joint (THO-TMJ), which causes obvious restriction of mouth opening and maxillofacial malformation, remain unclear. In this study, our findings demonstrated that injured chondrocytes in the condylar cartilage, but not osteoblasts in the injured subchondral bone, played definite roles in the development of THO-TMJ in mice. Injured condylar chondrocytes without articular disc reserves might secrete growth factors, such as IGF1 and TGFß2, that stimulate precursor cells, such as endothelial cells and muscle-derived cells, to differentiate into chondrocytes or osteoblasts and induce THO-TMJ. Preserved articular discs can alleviate the pressure on the injured cartilage and inhibit the development of THO-TMJ by inhibiting the secretion of these growth factors from injured chondrocytes. However, the exact molecular relationships among trauma, the injured condylar cartilage, growth factors such as TGFß2, and pressure need to be explored in detail in the future.

Front Pharmacol ; 11: 592, 2020.
Article En | MEDLINE | ID: mdl-32431614

Parathyroid hormone (PTH) is crucial for bone remodeling. Intermittent PTH (1-34) administration stimulates osteogenesis and promotes bone formation; however, the possible targets and underlying mechanisms still remain unclear. In this study, functional links between PTH and Foxc1, a transcription factor reported to be predominant in skeletal development and formation, were indicated. We determined the impacts of Foxc1 on in vitro osteogenic differentiation and in vivo bone regeneration under intermittent PTH induction, and further explored its possible targets. We found that the expression level of Foxc1 was upregulated during osteogenic induction by intermittent PTH treatment, and the elevated expression of Foxc1 induced by PTH was inhibited by PTH1R silencing, while rescued by intermittent PTH supplement. By gain- and loss-of-function strategies targeting Foxc1 in MC3T3-E1 cells, we demonstrated that Foxc1 could promote in vitro osteogenic differentiation by intermittent PTH induction. Moreover, immunofluorescence analysis indicated the nuclear co-localization of Foxc1 with Runx2. Luciferase-reporter and chromatin immunoprecipitation analysis further confirmed that Foxc1 could bind to the P1 promoter region of Runx2 directly, which plays an indispensable part in osteogenic differentiation and bone mineralization. Meanwhile, we also revealed that Foxc1 could promote bone regeneration induced by intermittent PTH treatment in vivo. Taken together, this study revealed the role and mechanism of Foxc1 on in vitro osteogenic differentiation and in vivo bone regeneration in response of intermittent PTH treatment.

Curr Neuropharmacol ; 18(12): 1180-1186, 2020.
Article En | MEDLINE | ID: mdl-32348227

Hypoxic-ischemic (HI) brain injury is a leading cause of acute mortality and chronic disability in newborns. Current evidence shows that cerebral microvascular response and compromised blood-brain barrier (BBB) integrity occur rapidly and could primarily be responsible for the brain injury observed in many infants with HI brain injury. MicroRNAs (miRNAs) are a type of highly conserved non-coding RNAs (ncRNAs), which consist of 21-25 nucleotides in length and usually lead to suppression of target gene expression. Growing evidence has revealed that brainenriched miRNAs act as versatile regulators of BBB dysfunctions in various neurological disorders including neonatal HI brain injury. In the present review, we summarize the current findings regarding the role of miRNAs in BBB impairment after hypoxia/ischemia brain injury. Specifically, we focus on the recent progress of miRNAs in the pathologies of neonatal HI brain injury. These findings can not only deepen our understanding of the role of miRNAs in BBB impairment in HI brain injury, but also provide insight into the development of new therapeutic strategies for preservation of BBB integrity under pathological conditions.

BMC Pharmacol Toxicol ; 20(1): 62, 2019 10 29.
Article En | MEDLINE | ID: mdl-31665091

BACKGROUND: Cardiovascular events (CVEs) was considered as one of the primary cause to reduce the quality of life in breast cancer patients with aromatase inhibitors (AIs) treatment, which has not been sufficiently addressed. The aim of this study was to assess the correlation between risk of CVEs and AIs in patients with breast cancer. METHODS: Included studies were obtained from the databases of Embase, Pubmed, Cochrane Library, Clinical, and reference lists. The main outcome measures were overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Furthermore, the association and the risk differences among different tumor types, AIs,ages,or treatment regimens were conducted. Fixed-effect or random-effect models were applied in the statistical analyses according to the heterogeneity. Our analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Seventeen studies, which included 44,411 subjects, were included in our analyses. The overall incidence of CVEs in AIs group was 13.02% (95% CI: 8.15-20.17%) and almost all of the high-grade CVEs occurred in patients treated with AIs. The pooled ORs of CVEs was 0.9940 (95% CI: 0.8545-1.1562). Under sub-group analysis, the incidence of CVEs related to exemestane was higher than that of controls (OR = 1.1564, 95% CI: 1.0656-1.2549), but no statistical differences in risk of CVEs were found in other sub-group analysis. No evidence of publication bias was found for incidence of CVEs in our meta-analysis by a funnel plot. CONCLUSIONS: These results suggest that patients with breast cancer treated with AIs do not have a significant risk of developing CVEs in comparison with the controls, and exemestane might not be considered as the alternative AI to the breast cancer patients from the perspective of CVEs. Further studies are recommended to investigate this association and the risk differences among different tumor types, AIs or treatment regimens.

Antineoplastic Agents, Hormonal/adverse effects , Aromatase Inhibitors/adverse effects , Breast Neoplasms/drug therapy , Cardiovascular Diseases/chemically induced , Female , Humans , Risk
J Hum Genet ; 64(9): 875-883, 2019 Sep.
Article En | MEDLINE | ID: mdl-31273320

Micrognathia is a common craniofacial deformity which represents hypoplastic development of the mandible, accompanied by retrognathia and consequent airway problems. Usually, micrognathia is accompanied by multiple systematic defects, known as syndromic micrognathia, and is in close association with genetic factors. Now, large quantities of pathogenic genes of syndromic micrognathia have been revealed. However, how these different pathogenic genes could lead to similar phenotypes, and whether there are some common characteristics among these pathogenic genes are still unknown. In this study, we proposed a genetic-phenotypic classification of syndromic micrognathia based on pathogenic genes information obtained from Phenolyzer, DAVID, OMIM, and PubMed database. Pathogenic genes of syndromic micrognathia could be divided into four groups based on gene function, including cellular processes and structures, cell metabolism, cartilage and bone development, and neuromuscular function. In addition, these four groups exhibited various clinical characteristics, and the affected systems, such as central nervous system, skeletal system, cardiovascular system, oral and dental system, respiratory system and muscle, were different in these four groups. This classification could provide meaningful insights into the pathogenesis of syndromic micrognathia, and offer some clues for understanding the molecular mechanism, as well as guiding precise clinical diagnosis and treatment for syndromic micrognathia.

Mandible/pathology , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Phenotype , Humans , Syndrome
J Craniofac Surg ; 30(8): e737-e740, 2019.
Article En | MEDLINE | ID: mdl-31306377

OBJECTIVE: The purpose of this study was to quantitatively investigate the long-term effects of augmented corticotomy-assisted orthodontics in adult patients with alveolar defect in mandibular anterior region. MATERIALS AND METHODS: Thirty lower incisors with alveolar defect on the labial sides were included in this study from 10 adult patients received augmented corticotomy-assisted orthodontics in mandibular anterior region. Cone-beam computed tomography images were obtained before orthodontic treatment (T0), 3 months after augmented corticotomy (T1) and 2 years after removal of orthodontic appliance (T2). Measurements of variables at different time points were compared using Student-Newman-Keuls test. RESULTS: Each patient completed augmented corticotomy-assisted orthodontics successfully. In the 30 subjects studied, root length and bone thickness on the labial side at 1/2 root length level were maintained from T0 to T2 (P >.05). Bone thickness at 3/4 root length level increased from T0 to T1 (P <.001), then decreased from T1 to T2 (P <.001), and which of T2 is greater than that of T0 (P <.001). Bone thickness at root apex level increased from T0 to T1 (P <.001), and remained steady from T1 to T2 (P >.05). CONCLUSIONS: Augmented corticotomy-assisted orthodontics is a promising approach for the treatment of adult patients with alveolar defect, which showed stable long-term effect of bone augmentation and minimal periodontal iatrogenic sequelae during treatment.

Mandible/diagnostic imaging , Cone-Beam Computed Tomography , Humans , Incisor , Orthodontic Appliances , Time Factors
Acta Biochim Biophys Sin (Shanghai) ; 51(6): 588-597, 2019 Jun 20.
Article En | MEDLINE | ID: mdl-31089719

The forkhead transcription factor C1 (Foxc1) is a cell-fate-determining factor that controls cranial bone development and osteogenic differentiation. Previously, it was demonstrated that various microRNAs (miRNAs) play important roles in osteogenesis and regulate the complex process of osteogenic differentiation. However, it remains unclear how miRNA expression changes during Foxc1-promoted osteogenic differentiation. In this study, we successfully overexpressed the Foxc1 gene in MC3T3-E1 cells and investigated the alterations in the miRNA expression profile on day 3 after osteogenic induction by using a miRNA microarray. Nine downregulated miRNAs and eight upregulated miRNAs were found to be differentially expressed. Among these miRNAs, miR-103-3p was consistently downregulated in the Foxc1-overexpressing MC3T3-E1 cells and was identified as a negative regulator of osteogenic differentiation by using a gain- and lose-of-function assay. The special AT-rich sequence-binding protein 2 (Satb2), a pivotal osteogenic transcription factor, was identified as the miR-103-3p targeting gene and was verified by real-time polymerase chain reaction, western blot analysis, and luciferase assay. Overexpression of miR-103-3p markedly inhibited the expression of Satb2 and attenuated Foxc1-promoted osteogenic differentiation. Taken together, our results elucidated the miRNA expression profiles of MC3T3-E1 cells in the early stage of Foxc1-promoted osteogenic differentiation and suggested that miR-103-3p acts as a negative regulator of the osteogenic differentiation of MC3T3-E1 cells by directly targeting Satb2.

Cell Differentiation/genetics , Forkhead Transcription Factors/genetics , Gene Expression Regulation , Matrix Attachment Region Binding Proteins/genetics , MicroRNAs/genetics , Osteogenesis/genetics , Transcription Factors/genetics , Animals , Cell Line , Forkhead Transcription Factors/metabolism , Gene Expression Profiling/methods , Matrix Attachment Region Binding Proteins/metabolism , Mice , Osteoblasts/cytology , Osteoblasts/metabolism , Transcription Factors/metabolism
J Craniomaxillofac Surg ; 47(7): 1155-1161, 2019 Jul.
Article En | MEDLINE | ID: mdl-30890399

PURPOSE: The exact development process underlying traumatic heterotopic ossification of the temporomandibular joint (THO-TMJ) is largely unclear. In this study, we try to explore the histological development process of THO-TMJ. MATERIALS AND METHODS: Condylar cartilage of one-month-old male mice was partially removed from the left joint with small scissors to induce THO-TMJ. The phenotypes were observed using gross observation, microcomputed tomography (micro-CT) scans and histological examination from one month to six months after surgery. RESULTS: The micro-CT examination results showed that the injured condyle integrated with ectopic bone tissue to form an osteophyte and that the volume and density of the osteophyte grew exponentially with time. Hematoxylin and eosin (H&E), safranin O and fast green staining of the THO-TMJ specimens revealed that the ectopic bone tissue was mainly nonmineralized fibrous tissue 1 month after surgery. This tissue gradually transformed into cartilage 3 months after surgery. Finally, the tissues transformed into mature bone tissue 6 months after surgery. Immunofluorescence staining showed VEGF-α expression in the heterotopic tissue 1 month after surgery, and the expression of Sox9 in the heterotopic tissue was obvious 3 months after surgery. Furthermore, OCN expression was evident in most of the heterotopic tissue 6 months after surgery. The results also showed clear hypoxia-inducible factor 1-alpha (Hif-1α) expression in the injured chondrocytes of the condyle, especially in the articular proliferative zone and fibrocartilaginous zone. CONCLUSIONS: The THO-TMJ imaging characteristics indicated an exponential change with time. Histologically, the development process of THO-TMJ is an endochondral ossification process and includes three stages, fibroproliferative, chondrogenic and osteogenic stage. In addition, Hif-1α, which was expressed in some of the injured chondrocytes, may play an essential role in the initial THO-TMJ.

Ossification, Heterotopic , Temporomandibular Joint , Animals , Chondrocytes , Chondrogenesis , Male , Mandibular Condyle , Mice , X-Ray Microtomography