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.

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.

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.

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.

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.

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.

Lack of association between the Angiogenin (ANG) rs11701 polymorphism and amyotrophic lateral sclerosis risk: a meta-analysis.

To perform a meta-analysis to help resolve the controversy of whether the Angiogenin (ANG) rs11701 polymorphism is associated with amyotrophic lateral sclerosis (ALS) risk. A literature search of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and SinoMed was conducted for eligible studies published up to Jun 5, 2015. The strength of the association between the polymorphism and ALS susceptibility was estimated by odds ratio (OR) and associated 95 % confidence interval (CI). The pooled ORs were assessed for the dominant model (TG + GG vs. TT), recessive model (GG vs. TG + TT), heterozygote model (TG vs. TT), homozygote model (GG vs. TT) and allele model (G vs. T). Ten eligible articles were identified, which reported 14 case-control studies and a total of 5807 cases and 3861 controls. Analysis of pooled ORs and 95 % CIs suggested lack of association between the ANG rs11701 polymorphism and risk for ALS, Familial ALS or Sporadic ALS (all p value for z test >0.05). A stratified analysis according to Caucasian or Han Chinese origin further showed that the rs11701 polymorphism was not associated with the disease risk in Caucasians or Han Chinese. There is no difference in the polymorphism frequencies between patients with FALS or SALS. The ANG rs11701 polymorphism was not associated with risk for ALS, FALS or SALS. There is no difference between the polymorphism frequencies in patients with FALS or SALS. Further well-designed studies with larger populations are required to validate these results.

Lack of association between the ATP13A2 A746T variant and Parkinson's disease susceptibility in Han Chinese: a meta-analysis.

PURPOSE: To perform a meta-analysis to help resolve the controversy of whether the ATP13A2 A746T variant is associated with Parkinson's disease (PD) susceptibility in Han Chinese. METHODS: Six literature databases were searched for case-control studies published up to October 2014: Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang and SinoMed. RESULTS: Five eligible articles were identified, which reported six case-control studies and a total of 1703 cases and 2050 controls. The overall results suggested low frequencies of the A746T variant in Han Chinese patients (9/1703, 0.55%) and controls (6/2050, 0.29%). We failed to find evidence of significant differences in variant frequencies among Han Chinese, Uyghur and Japanese patients (p = 0.263). Analysis of pooled odds ratios (ORs) and 95% confidence interval (CIs) revealed no association between the A746T variant and overall PD risk (GA vs. GG: OR 1.78, 95%CI 0.71-4.46, p = 0.216; allele A vs. G: OR 1.90, 95%CI 0.77-4.69, p = 0.167). CONCLUSION: The ATP13A2 A746T variant is rare in Han Chinese patients and controls and is not associated with PD susceptibility in this ethnic group. Variant frequencies do not differ significantly among Han Chinese, Uyghur and Japanese patients. Further well-designed studies with larger samples are needed to validate these results.

[Tuberous sclerosis complex with refractory epilepsy: a clinicopathologic study of 14 cases].

OBJECTIVE: To study the clinicopathologic features of tuberous sclerosis complex (TSC). METHODS: The clinicopathologic data of the patients diagnosed as TSC with refractory epilepsy and resection of epileptic focus were retrospectively analyzed. RESULTS: Fourteen cases were included, the mean age was (15.8±12.9) years, with a male predominance (male to female ratio=10:4). Frontal lobe was the most common (13/14) site of involvement. MRI showed multiple patchy long T1 and long T2 signals. CT images showed multiple subependymal high density calcified nodules in nine cases. Histology showed mild to severe disruption of the cortical lamination, cortical and subcortical tubers with giant cells and/or dysmorphic neurons. The giant cells showed strong immunoreactivity for vimentin and nestin, while the dysmorphic neurons partially expressed MAP2 and NF. Vimentin also stained strongly the "reactive" astrocytes. Thirteen cases had follow-up information: Engel class I in six cases, Engel class II in six cases, and Engel class III in one case. CONCLUSIONS: Diagnosis of TSC relies on combined pathologic, clinical and neuroradiological features. Immunohistochemical staining can be helpful. Resection of epileptic focus is an effective method to treat refractory epilepsy in TSC.

[Research on Application of Fourier Transform Infrared Spectrometry in the Diagnosis of Lymph Node Metastasis in Gastric Cancer].

To explore the feasibility of quick intraoperative in situ and noninvasive diagnosis of lymph node metastasis in gastric cancer by Fourier transform infrared (FTIR) spectrometry. FTIR spectra of surgically removed fresh lymph nodes were measured by FTIR via probe of attenuated total reflection (ATR). For each spectrum, 13 bands were indentified and assigned between 3 000 and 1 000 cm(-1). Peaks in the spectra were measured and relative intensity ratios were calculated and compared between the spectra of Metastatic lymph nodes (MLN) and Non-metastatic lymph nodes (NMLN). Standard statistic analysis was performed. 720 lymph nodes were measured in 38 gastric cancer patients. Results show that there were significant differences between the FTIR of 540 MLN and 180 NMLN. (1) For the band related to nucleic acid: The ratios of I1240/I1460 (p = 0.015) and I1080/I1460 (p = 0.034) increased in MLN, which shows that the relative quantity of nucleic acid was more in MLN than that in NMLN. (2) For the bands related to protein: The ratios of I1640 /I1460 (p = 0.001) and I146/I1460 (p = 0.027) increased in MLN, which shows that the relative quantity of protein was more in MLN. (3) For the bands related to lipid: The ratio of I2855/I460 and I1740/I1460 decreased in MLN FTIR spectrum, indicating the lower relative quantity of lipid in MLN. (4) For the bands related to carbohydrate: The ratio of I1160/I1460 (p = 0.023) decreased in MLN FTIR spectrum, indicating the lower relative quantity of carbohydrate in MLN. The results demonstrate that the FTIR spectroscopy technique maybe develop into a promising method for in situ and quick intraoperative differential diagnosis of lymph node metastasis in gastric cancer.

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.

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.

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.].

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.

Simvastatin induces estrogen receptor-alpha expression in bone, restores bone loss, and decreases ERα expression and uterine wet weight in ovariectomized rats.

We previously reported that simvastatin induces estrogen receptor-alpha (ERα) in murine bone marrow stromal cells in vitro. In this study, we investigated the effect of simvastatin on ERα expression in bone and uterus in ovariectomized (OVX) rats and evaluated bone mass, bone strength, and uterine wet weight. Three-month-old Sprague-Dawley female rats received OVX or sham operation. Six weeks later, the rats were treated orally with simvastatin (5 or 10 mg/kg/day), or intraperitoneally with 17-ß-estradiol (E(2)) or a combination of simvastatin and E(2) for 6 weeks. Uterine wet weight, bone mineral density (BMD) of lumbar vertebrae, biomechanics of lumbar vertebrae, and induction of ERα expression in the bone and uterus were analyzed. The 6-week simvastatin treatment improved lumbar vertebral BMD and boosted biomechanical performance of the vertebral body compared to the OVX control, suggesting that simvastatin can treat osteoporosis caused by estrogen deficiency. More interestingly, simvastatin could increase ERα expression and synergy with estradiol in bone while antagonizing estradiol in the uterus, along with uterus atrophy and uterine wet weight decreases. In conclusion, these data suggest that simvastatin exert opposing modulatory effects on ERα expression on bone and uterus in ovariectomized rats, inducing ERα expression and synergy with estrogen to perform anabolic effects on the bones while decreasing E2 efficacy and uterine wet weight. This finding may be helpful to explain the mechanism of statin treatment in osteoporosis caused by estrogen deficiency.

[Abnormal expression and significance of MIR-184 in human renal carcinoma].

OBJECTIVE: To explore the role of microRNA-184(MIR-184) in the development of renal cell carcinoma(RCC). METHODS: The expressions of MIR-184 in 51 patients with RCC Investigated, normal adjacent tissues (ADTs) matched by fluorescence quantitative PCR technology (RT-qPCR) and the correlations analyzed between MIR-184 expression and the age, gender and clinical stage of RCC patients. RESULTS: The average expression of MIR-184 in RCC was -14.664 6 ± 5.362 4, while that in ADTs was -10.408 7 ± 3.482 7(P<0.01). Bounded with the MIR-184 expression in RCC, patients were divided into lower-expression group and higher-expression group. Meanwhile, the RCC patients were divided into three groups according to the age, gender and clinical stage of the patients. Chi-square statistical analysis showed that the expression level of MIR-184 was not significantly correlated with the patient's age, gender and clinical stage (respectively: P>0.03, P>0.99, P>0.03). CONCLUSION: MIR-184 in RCC was significantly lower than that in ADTs, which may have potential significance in the occurrence and development of RCC.

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.

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.

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.