Sodium-glucose cotransporter 2 inhibitors attenuate vascular calcification by suppressing endoplasmic reticulum protein thioredoxin domain containing 5 dependent osteogenic reprogramming.

AIMS: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved. METHODS AND RESULTS: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models. CONCLUSIONS: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.

Anomalous origin of the coronary artery: prevalence and coronary artery disease in adults undergoing coronary tomographic angiography.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital coronary anomaly with the potential to cause adverse cardiac events. However, there is limited data on the association between AAOCA and coronary artery disease (CAD). Therefore, the aim of this study is to determine the prevalence and symptoms of patients with AAOCA, as well as investigate the correlation between AAOCA and CAD in a population referred for coronary computed tomographic angiography (CTA). METHODS AND RESULTS: All consecutive patients who underwent CTA from 2010 to 2021 were included. Characteristics, symptoms, coronary related adverse events and CTA information were reviewed by medical records. Separate multivariable cumulative logistic regressions were performed, using the stenosis severity in each of the four coronaries as individual responses and as a combined patient clustered response. Finally, we identified 207 adult patients with AAOCA, the prevalence of AAOCA is 0.23% (207/90,501). Moreover, this study found no significant association between AAOCA and CAD. AAOCA did not contribute to higher rates of hospitalization or adverse cardiac events, including calcification. CONCLUSION: AAOCA is a rare congenital disease that is not associated with increased presence of obstructive CAD in adults.

ANXA9 facilitates S100A4 and promotes breast cancer progression through modulating STAT3 pathway.

Breast cancer has the highest global incidence and mortality rates among all cancer types. Abnormal expression of the Annexin family has been observed in different malignant tumors, including upregulated ANXA9 in breast cancer. We found highly expressed ANXA9 in metastatic breast cancer tissues, which is correlated with breast cancer progression. In vitro, the functional experiments indicated ANXA9 influenced breast cancer proliferation, motility, invasion, and apoptosis; in vivo, downregulation of ANXA9 suppressed breast cancer xenograft tumor growth and lung metastasis. Mechanically, on one side, we found that ANXA9 could mediate S100A4 and therefore regulate AKT/mTOR/STAT3 pathway to participate p53/Bcl-2 apoptosis; on the other side, we found ANXA9 transferred S100A4 from cells into the tumor microenvironment and mediated the excretion of cytokines IL-6, IL-8, CCL2, and CCL5 to participate angiogenesis via self- phosphorylation at site Ser2 and site Thr69. Our findings demonstrate significant involvement of ANXA9 in promoting breast cancer progression, thereby suggesting that therapeutic intervention via targeting ANXA9 may be effective in treating metastatic breast cancer.

B-type natriuretic peptide levels at admission predict the prognosis of patients with infective endocarditis undergoing cardiac surgery.

Purpose: The objective of this study was to explore the relationship between elevated B-type natriuretic peptide (BNP) levels and the prognosis of patients with infective endocarditis (IE) undergoing cardiac surgery. Methods: In total, 162 IE patients with recorded BNP levels upon admission were included in the present study. The primary end point was all-cause mortality. Results: Multivariate Cox analysis revealed a significant association between log BNP and all-cause mortality. Kaplan-Meier analysis revealed a poorer prognosis for patients with BNP levels ≥ the 75th percentile. Furthermore, the linear trend test indicated a significant link between BNP quartiles and the primary end point within the models. Conclusion: Elevated BNP levels upon admission could predict all-cause mortality in IE patients undergoing cardiac surgery.

Infective endocarditis (IE) refers to an infection affecting the heart lining, heart valves or blood vessels. Despite advancements in medical and surgical interventions, the overall mortality rate remains high among IE patients after surgery. B-type natriuretic peptide (BNP) is a peptide released in response to increased stress on the ventricular and atrial walls and is commonly used as a biomarker for heart failure. This study was aimed to assess the potential of BNP in predicting all-cause mortality in IE patients. The results indicate that elevated BNP levels upon admission could predict a worse prognosis following endocarditis surgery. Additionally, elevated BNP levels upon admission were associated with an increased risk of death.

MSEF-Net: Multi-scale edge fusion network for lumbosacral plexus segmentation with MR image.

Nerve damage of spine areas is a common cause of disability and paralysis. The lumbosacral plexus segmentation from magnetic resonance imaging (MRI) scans plays an important role in many computer-aided diagnoses and surgery of spinal nerve lesions. Due to the complex structure and low contrast of the lumbosacral plexus, it is difficult to delineate the regions of edges accurately. To address this issue, we propose a Multi-Scale Edge Fusion Network (MSEF-Net) to fully enhance the edge feature in the encoder and adaptively fuse multi-scale features in the decoder. Specifically, to highlight the edge structure feature, we propose an edge feature fusion module (EFFM) by combining the Sobel operator edge detection and the edge-guided attention module (EAM), respectively. To adaptively fuse the multi-scale feature map in the decoder, we introduce an adaptive multi-scale fusion module (AMSF). Our proposed MSEF-Net method was evaluated on the collected spinal MRI dataset with 89 patients (a total of 2848 MR images). Experimental results demonstrate that our MSEF-Net is effective for lumbosacral plexus segmentation with MR images, when compared with several state-of-the-art segmentation methods.

Impact of coronary artery disease in patients with hypertrophic cardiomyopathy.

BACKGROUND: Atherosclerotic coronary artery disease (CAD) often occurs concurrently with hypertrophic cardiomyopathy (HCM). However, the influence of concomitant CAD has not been fully assessed in patients with HCM. METHODS: Invasive or computed tomography coronary angiography was performed in 461 patients with HCM at our hospital to determine the presence and severity of CAD from March 2010 to April 2022. The primary end points were all-cause, cardiovascular, and sudden cardiac deaths. The survival of HCM patients with severe CAD was compared with that of HCM patients without severe CAD. RESULTS: Of 461 patients with HCM, 235 had concomitant CAD. During the median (interquartile range) follow-up of 49 (31-80) months, 75 patients (16.3%) died. The 5-year survival estimates were 64.3%, 82.5%, and 86.0% for the severe, mild-to-moderate, and no-CAD groups, respectively (log-rank, p = 0.010). Regarding the absence of cardiovascular death, the 5-year survival estimates were 68.5% for patients with severe CAD, 86.4% for patients with mild-to-moderate CAD, and 90.2% for HCM patients with no CAD (log-rank, p = 0.001). In multivariate analyses, severe CAD was associated with all-cause and cardiovascular death after adjusting for age, left ventricular ejection fraction, hypertension, and atrial fibrillation. CONCLUSIONS: This study showed a worse prognosis among HCM patients with severe CAD than among HCM patients without severe CAD. Therefore, timely recognition of severe CAD in HCM patients and appropriate treatment are important.

Characterizing the Survival-Associated Interactions Between Tumor-Infiltrating Lymphocytes and Tumors From Pathological Images and Multi-Omics Data.

The tumor-infiltrating lymphocytes (TILs) and its correlation with tumors have shown significant values in the development of cancers. Many observations indicated that the combination of the whole-slide pathological images (WSIs) and genomic data can better characterize the immunological mechanisms of TILs. However, the existing image-genomic studies evaluated the TILs by the combination of pathological image and single-type of omics data (e.g., mRNA), which is difficulty in assessing the underlying molecular processes of TILs holistically. Additionally, it is still very challenging to characterize the intersections between TILs and tumor regions in WSIs and the high dimensional genomic data also brings difficulty for the integrative analysis with WSIs. Based on the above considerations, we proposed an end-to-end deep learning framework i.e., IMO-TILs that can integrate pathological image with multi-omics data (i.e., mRNA and miRNA) to analyze TILs and explore the survival-associated interactions between TILs and tumors. Specifically, we firstly apply the graph attention network to describe the spatial interactions between TILs and tumor regions in WSIs. As to genomic data, the Concrete AutoEncoder (i.e., CAE) is adopted to select survival-associated Eigengenes from the high-dimensional multi-omics data. Finally, the deep generalized canonical correlation analysis (DGCCA) accompanied with the attention layer is implemented to fuse the image and multi-omics data for prognosis prediction of human cancers. The experimental results on three cancer cohorts derived from the Cancer Genome Atlas (TCGA) indicated that our method can both achieve higher prognosis results and identify consistent imaging and multi-omics bio-markers correlated strongly with the prognosis of human cancers.

Low-Dose CT Denoising via Sinogram Inner-Structure Transformer.

Low-Dose Computed Tomography (LDCT) technique, which reduces the radiation harm to human bodies, is now attracting increasing interest in the medical imaging field. As the image quality is degraded by low dose radiation, LDCT exams require specialized reconstruction methods or denoising algorithms. However, most of the recent effective methods overlook the inner-structure of the original projection data (sinogram) which limits their denoising ability. The inner-structure of the sinogram represents special characteristics of the data in the sinogram domain. By maintaining this structure while denoising, the noise can be obviously restrained. Therefore, we propose an LDCT denoising network namely Sinogram Inner-Structure Transformer (SIST) to reduce the noise by utilizing the inner-structure in the sinogram domain. Specifically, we study the CT imaging mechanism and statistical characteristics of sinogram to design the sinogram inner-structure loss including the global and local inner-structure for restoring high-quality CT images. Besides, we propose a sinogram transformer module to better extract sinogram features. The transformer architecture using a self-attention mechanism can exploit interrelations between projections of different view angles, which achieves an outstanding performance in sinogram denoising. Furthermore, in order to improve the performance in the image domain, we propose the image reconstruction module to complementarily denoise both in the sinogram and image domain.

Residual-atrous attention network for lumbosacral plexus segmentation with MR image.

Accurate segmentation of the lumbosacral plexus is a crucial step for diagnosis and analysis of nerve damage in clinical. Due to the extremely low contrast and complicated structure around the lumbosacral plexus, it has been remaining a challenging task to effectively segment the lumbosacral plexus from spinal MR images. Even though several deep learning methods for spine segmentation have been developed, most of them only pay attention to the segmentation of vertebral bodies and intervertebral discs rather than nerves. To solve these problems, in this paper, we propose a residual-atrous attention network (RA2-Net) for lumbosacral plexus segmentation with MR images. Specifically, the RA2-Net consists of three main parts, (1) the atrous encoder module is employed to learn multi-scale contextual features from MR images in the encoder, (2) the residual skip connection operation is used to integrate the features with high-resolution spatial details in the encoder and the high-level contextual features in the decoder, and (3) the scale attention block is proposed for fusing the multi-scale high-level features in the decoder. We perform our proposed RA2-Net for the lumbosacral plexus segmentation on the collected spinal MRI dataset with 10 patients (a total of 236 MRI scans). Extensive experiments demonstrate that our RA2-Net achieves better performance in lumbosacral plexus segmentation with MR images when compared with several state-of-the-art methods.

Bombesin receptor-activated protein exacerbates cisplatin-induced AKI by regulating the degradation of SIRT2.

BACKGROUND: Acute kidney injury (AKI) is a public health problem with no specific therapies in the clinic and the underlying pathogenesis of AKI remains obscure. Bombesin receptor-activated protein (BRAP, C6ORF89 protein) was initially discovered as a ligand for a previously orphan G-protein-coupled receptor bombesin-like receptor-3. At present, accepted biological effects of BRAP include cell cycle progression, wound repair and the activation of histone deacetylases. However, its role in kidney disease is unknown. In this study we have investigated the role of BRAP and underlying mechanisms involved in cisplatin (CP)-induced AKI. METHODS: Here we used Bc004004 (homologous of C6ORF89 in mice) knockout mice and HK2 cells to investigate the effect of BRAP on AKI in vitro and in vivo. We analyzed ChIP-Seq and RNA-Seq data to search for the upstream regulators of BRAP and downstream mediators of BRAP action in AKI. Immunostaining, real-time polymerase chain reaction (PCR), co-immunoprecipitation, a dual-luciferase reporter assay and ChIP-PCR assay were applied to reveal the upstream and downstream regulation mechanism of BRAP during cisplatin-induced AKI. RESULTS: BRAP was downregulated in mice and human kidneys with AKI. Global Bc004004 deletion alleviated tubular cell apoptosis and necroptosis in CP-induced AKI mice, whereas local overexpression of BRAP in kidneys aggravated them. Pan-caspase inhibitor Z-VAD pretreatment attenuated CP-induced blood creatinine increase and kidney injury in wild-type mice but not in BRAP -/- mice. The activation of mixed lineage kinase like-domain was magnified by Z-VAD in CP-treated mice, especially in BRAP -/- mice. The cytoprotective effect of Z-VAD was more substantial than necrostatin-1 (Nec-1, an inhibitor of necroptosis) in CP-treated human kidney proximal tubular epithelial (HK2) cells. Furthermore, Nec-1 pretreatment reduced the CP-induced cell death in BRAP overexpression HK2 cells but did not work in cells with normal BRAP levels. We determined that CP treatment activated the nuclear factor-κB subunit P65 and inhibition of P65 increased the messenger RNA (mRNA) levels of BRAP in HK2 cells. The chromatin immunoprecipitation assay and dual-luciferase reporter gene assay verified P65 binding to the C6ORF89 promoter and reduced its mRNA expression upon CP treatment. Next we found that sirtuin 2 (SIRT2) was downregulated in CP-induced AKI and BRAP levels directly impacted the protein levels of SIRT2. Our findings further confirmed that BRAP regulates the SIRT2 protein levels by affecting SIRT2's interactions with E3 ubiquitin ligase HRD1 and subsequent proteasomal degradation. CONCLUSIONS: Our results demonstrated that BRAP played an important role in tubular cell apoptosis and necroptosis during CP-induced AKI. Safe and efficient BRAP inhibitors might be effective therapeutic options for AKI.

Comparison of two internal fixation systems in lumbar spondylolysis by finite element methods.

BACKGROUND AND PURPOSE: Internal fixation surgeries are currently the most effective treatments for lumbar spondylolysis, but the optimal fixation method is still on debate. This study was designed to compare the biomechanical characteristics of two fixation methods for lumbar spondylolysis, the pedicle screw-U shape rod (PSUSR) internal fixation system, and the pedicle screw-vertebral plate hook (PSVPH) internal fixation system, through three-dimensional finite element analysis, expecting to provide clinical guidance. METHODS: Four finite element models (A, B, C, D) of L4-S1 vertebral body of a female patient were reconstructed by CT image segmentation. (A: intact model. B: spondylolysis model. C: spondylolysis model with PSUSR internal fixation. D: spondylolysis model with PSVPH internal fixation). Six physiological motion states were simulated by applying 500N concentrated force and 10Nm moment load to four models. The biomechanical advantages of the two internal fixation systems were evaluated by comparing the range of motion (ROM), maximum stress, maximum strain, and maximum displacement of the models. RESULTS: Compared to model B, the ROM decreased by 35.7%-57.1% in model C and 39.7%-64.8% in model D. The maximum displacements of model C and D both decreased. The maximum stresses in both vertebral and the internal fixation system are greater in model C than those in model D. The maximum stress and strain reduction of L5-S1 intervertebral disc in model D was greater than that in model C. Model D restores the articular cartilage stresses to the normal levels of model A. The maximum stress and maximum displacement of the bone graft in model C are greater than those in model D. CONCLUSIONS: The PSVPH internal fixation system has better biomechanical properties than PSUSR internal fixation system in several mechanical comparisons. Experimental results suggest that PSVPH internal fixation system can effectively treat lumbar spondylolysis while preserving segmental mobility, and can be the treatment of choice.

A Triple-Regulated Oncolytic Adenovirus Carrying MicroRNA-143 Exhibits Potent Antitumor Efficacy in Colorectal Cancer.

The cancer-targeting gene virotherapy might be a useful strategy for the treatment of cancer, because it could combine the advantages of both gene therapy and virotherapy. This study aimed to construct a triple-regulated oncolytic adenovirus, Ad-RGD-Survivin-ZD55-miR-143, carrying the therapeutic gene miR-143 and evaluate its possible antitumor effect in colorectal cancer. We observed that miR-143 was lowly expressed in patients with colorectal cancer. The upregulation of miR-143 could inhibit cell proliferation and induce cell apoptosis by targeting KRAS in colorectal cancer cells. Then, Ad-RGD-Survivin-ZD55-miR-143 was successfully constructed in this study. Cells infected with Ad-RGD-Survivin-ZD55-miR-143 could inhibit cell proliferation, suppress cell migration and invasion, arrest cells at the G1 phase, and induce cellular apoptosis. At the same time, Ad-RGD-Survivin-ZD55-miR-143 decreased the expression of PARP-1 and KRAS protein in vitro. In a HCT116 xenograft model, intratumoral injection of Ad-RGD-Survivin-ZD55-miR-143 resulted in reduced tumor growth. Furthermore, Ad-RGD-Survivin-ZD55-miR-143 induced apoptosis and decreased the expression level of KRAS in HCT116 xenograft cells. Our results suggested that Ad-RGD-Survivin-ZD55-miR-143 produced a strong antitumor effect by targeting KRAS and that this strategy could broaden the therapeutic options for treating colorectal cancer.

Thoracic vertebra fixation with a novel screw-plate system based on computed tomography imaging and finite element method.

BACKGROUND AND OBJECTIVE: The traditional pedicle screw-rod internal fixation system has been widely used for thoracic diseases in clinical practice, but its high profile increases the damage to soft tissue, leading to long-term intractable back stiffness. The purpose of this study is to compare biomechanical advantages between the new spine pedicle screw-plate internal fixation system and traditional pedicle screw-rod internal fixation system using finite element analysis. METHODS: Based on computed tomography (CT), four three-dimensional finite element models of T7-T9 were constructed. The downward concentrated force of 150 N and the moment of 5 Nm was applied to the models to simulate six physiological activities, including flexion, extension, left and right lateral bending, left and right axial torsion. The maximum displacement, range of motion (ROM) and maximum stress of the two models in six physiological activities, was measured to evaluate the biomechanical advantages of the novel pedicle screw-plate internal fixation system. RESULTS: The novel pedicle screw-plate internal fixation system has a lower profile than the traditional pedicle screw-rod internal fixation system. With regards to the stability, the maximum displacement of the models of two internal fixation systems decreased by 56.2%-91.4% under the six motion status when comparing with the unstable model. Meanwhile, the ROM remained unchanged between the two models of internal fixation systems besides the left lateral bending. However, there is no significant difference in the ROM between the models of the two internal fixation systems in left lateral bending motion (P = 0.203). In terms of the strength, the maximum stress in the model with the new pedicle screw-plate internal fixation system was higher than that of model with the traditional pedicle screw-rod internal fixation system in every motion status but left and right lateral bending motion. CONCLUSIONS: The novel pedicle screw-plate internal fixation system has lower profile in orthopedics and higher strength, However, it has no disadvantage when comparing with the traditional pedicle screw-rod internal fixation system in terms of the stability. In summary, we suggest that the novel spine pedicle screw-plate system can be used as a new internal fixation and provide better comfort for patients.

Modelling tri-cortical pedicle screw fixation in thoracic vertebrae under osteoporotic condition: A finite element analysis based on computed tomography.

BACKGROUND AND OBJECTIVE: The technique of tri-cortical pedicle screw (TCPS) has been used to improve the anchoring strength in the sacral vertebrae. However, no studies have reported their application in the thoracic vertebrae. Our research is aimed to assess the stability and strength of the TCPS in thoracic vertebrae under osteoporotic condition by three dimensional (3D) finite element method on the basis of medical image reconstruction using computed tomography (CT), and verifying its effectiveness in clinical application. MATERIALS AND METHODS: The 3D finite element models were constructed using Mimcs to transfer two dimensional CT images into 3D models by marching cubes algorithm of six-partition. Six physiological activities were simulated in 3D finite element models. Compared with the strength and stability of the uni-cortical pedicle screw (UCPS) and bi-cortical pedicle screw (BCPS), the effectiveness of TCPS was assessed. The stress distribution and maximum stress were measured to evaluate the strength. The maximum displacement and the range of motion were analysed to assessed the stability. EXPERIMENTAL RESULTS: Four geometrically accurate and nonlinear T7-T9 finite element models were constructed successfully by 3D finite element method based on the CT images. Three kinds of internal fixation methods in the osteoporotic thoracic vertebral body can improved the maximum stress, decrease the maximum displacement and range of motion in six physiological activities. The range of motion and maximum displacement of TCPS decreased more significantly than that of UCPS and BCPS. The maximum von Mises stress of TCPS was minimum and UCPS was maximum under the condition of extension, right lateral bending, left rotation and right rotation. CONCLUSIONS: Effectively, TCPS can provide better stability and strength than that of UCPS and BCPS techniques in the osteoporotic thoracic vertebrae. In practice, the technique of TCPS can be applied in the osteoporotic thoracic vertebral body to enhance the griping strength of the screws and reduce the risk of pedicle screw loosening. However, further cadaver experiments and more biomechanical analysis are necessary to confirmed our findings.

VGLL4 interacts with STAT3 to function as a tumor suppressor in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis, and there are no effective molecular-targeted drugs for TNBC patients in clinical practice. The JAK-STAT pathway is implicated in tumorigenesis and the progression of various cancers. In this study, the results demonstrated that VGLL4 is expressed at low levels in both TNBC specimens and cell lines and that VGLL4 expression is negatively correlated with Ki67 expression and tumor size in TNBC patients. VGLL4 knockdown can promote the growth of TNBC cells, while VGLL4 overexpression significantly suppresses the growth of TNBC cells in vitro. More importantly, VGLL4 significantly inhibits tumor progression in a nude mouse model. In addition, VGLL4 is a direct target of miR-454, and the upregulation of miR-454 decreases VGLL4 expression and promotes the cell growth of TNBC cells. Furthermore, we also demonstrated that VGLL4 interacts with STAT3, the core component of the JAK-STAT pathway, leading to the inactivation of STAT3 and the inhibition of STAT3 downstream transcription. Collectively, these findings indicate that VGLL4 expression is negatively associated with poor prognosis in TNBC patients. High expression of miR-454 may be one of the causes of the downregulation of VGLL4 in TNBC, and VGLL4 acts as a tumor suppressor in TNBC by interacting with STAT3 and subsequently suppresses the STAT3 signaling axis, providing potential biomarkers and therapeutic approaches for this fatal disease.

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells.

Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis.

The long noncoding RNA MIR210HG promotes tumor metastasis by acting as a ceRNA of miR-1226-3p to regulate mucin-1c expression in invasive breast cancer.

BACKGROUND: Long noncoding RNAs have been known to be involved in multiple types of malignancies, including invasive breast cancer (IBC). This study aimed to explore the role of long noncoding RNAs in IBC and elucidate the potential molecular mechanisms. METHODS: Using TCGA microarray data analysis, we identified a long noncoding RNA, MIR210HG, highly expressed in IBC. Kaplan-Meier method and the log-rank test were used for survival analysis. The gain-of-function experiments were performed to assess the function of MIR210HG in IBC invasion and migration in both in vitro and in vivo settings. Bioinformatic analysis as well as luciferase reporter assay, rescue experiments and western blot assay revealed the mode of action of MIR210HG. RESULTS: The aberrantly enhanced MiR210HG expression predicted poor prognosis and lower survival rate. Knockdown of MiR210HG suppressed IBC cell invasion and metastasis both in vitro and in vivo. MiR-1226-3p was identified and validated to be the target miRNA of MiR210HG. Furthermore, MiR210HG functions as a competing endogenous RNAs (ceRNA) which sponges miR-1226-3p, therefore upregulates the expression of mucin1 (MUC1-C). CONCLUSIONS: Our study demonstrated that MiR210HG sponges miR-1226-3p to facilitate invasive breast cancer cell invasion and metastasis by regulating mucin-1c and EMT pathway, revealing the oncogenic role of MiR210HG in IBC cells.

MiR-128-3p suppresses breast cancer cellular progression via targeting LIMK1.

Breast cancer is the most common malignancy in women all over the world. MiRNAs are a type of small noncoding RNA that can regulate various cellular processes via binding different target genes in cancer cells. In this study, we found that miR-128-3p could suppress cellular proliferation and motility abilities of breast cancer. In addition, we found that overexpression of miR-128-3p arrested breast cancer cells in G0/G1 phase by affecting expression of CDK4/CDK6/Cyclin D1 and CDK2/Cyclin E1. Furthermore, we confirmed that LIM domain kinase 1 (LIMK1) is a direct target gene of miR-128-3p and that overexpression of miR-128-3p could suppress the expression levels of LIMK1 and Cofilin 1, which is downstream of LIMK1. TCGA clinical database showed that miR-128-3p was highly expressed in breast cancer patients and that high expression of miR-128-3p indicates a better prognosis of breast cancer. Our findings demonstrated that miR-128-3p could regulate cellular progression of breast cancer via regulating the LIMK1/CFL1 signaling pathway, and this new avenue could broaden existing versions of molecular mechanisms in breast cancer and perhaps represent potential novel direction of breast cancer treatment in the future.

Overexpression of HDAC9 is associated with poor prognosis and tumor progression of breast cancer in Chinese females.

BACKGROUND: Breast cancer represents a serious health issue among females. HDAC9 has been identified as an oncogene in human cancers. This study sought to assess the prognostic value and the biologic function of HDAC9 in breast cancer patients. METHODS: Expression of HDAC9 in breast cancer tissues and cells was evaluated by quantitative real-time polymerase chain reaction. Kaplan-Meier survival analysis and Cox regression assay were conducted to explore the prognostic significance of HDAC9. Cell experiments were performed to investigate the effects of HDAC9 on the biologic behaviors of breast cancer cells. RESULTS: Expression of HDAC9 was significantly upregulated in both cancerous tissues and cells compared with the normal controls (all P<0.05). Overexpression of HDAC9 was correlated with lymph node metastasis (P=0.021) and TNM stage (P=0.004). Patients with high HDAC9 had poor overall survival compared to those with low levels of HDAC9 (log-rank P<0.05). Elevated HDAC9 was found to be an independent prognostic factor for the patients (hazard ratio=2.996, 95% CI=1.611-5.572, P=0.001). According to the cell experiments, tumor cell proliferation, migration and invasion were suppressed by knockdown of HDAC9. CONCLUSION: All data demonstrated that overexpression of HDAC9 serves as a prognostic biomarker and may be involved in the tumor progression of breast cancer.

Effects of verapamil on the pharmacokinetics of dihydromyricetin in rats and its potential mechanism.

1. This study investigates the effects of verapamil on the pharmacokinetics of dihydromyricetin in rats and clarifies its main mechanism. 2. The pharmacokinetic profiles of oral or intravenous administration of dihydromyricetin in Sprague-Dawley rats with or without pretreatment with verapamil were investigated. In addition, the effects of verapamil on the transport and metabolic stability of dihydromyricetin were investigated using Caco-2 cell transwell model and rat liver microsomes. 3. In the oral group, verapamil could significantly increase Cmax, and decrease oral clearance of dihydromyricetin (p < 0.05). In the intravenous group, the Cmax also increased compared with the control group, but the difference was not significant. However, the t1/2 and clearance rate decreased than that of the control (p < 0.05). The oral bioavailability increased significantly (p < 0.05) from 3.84% to 6.84% with the pretreatment of verapamil. A markedly higher transport of dihydromyricetin across the Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. Additionally, the intrinsic clearance rate of dihydromyricetin was decreased by the pretreatment with verapamil (27.0 versus 32.5 µL/min/mg protein). 4. Those results indicated that verapamil could significantly change the pharmacokinetic profiles of dihydromyricetin in rats, and it might exert these effects through increasing the absorption of dihydromyricetin by inhibiting the activity of P-gp, or through inhibiting the metabolism of dihydromyricetin in rat liver.