Dalbergia odorifera has been traditionally used as a medicine to treat many diseases. However, the role of 2,4,5-trimethoxyldalbergiquinol (TMDQ) isolated and extracted from D. odorifera in ...osteoblast function and the underlying molecular mechanisms remain poorly understood. The aim of this study was to investigate the effects and possible underlying mechanisms of TMDQ on osteoblastic differentiation of primary cultures of mouse osteoblasts as an in vitro assay system. TMDQ stimulated osteoblastic differentiation, as assessed by the alkaline phosphatase (ALP) activity, ALP staining, mineralized nodule formation, and the levels of mRNAs encoding the bone differentiation markers, including ALP, bone sialoprotein (BSP), osteopontin, and osteocalcin. TMDQ upregulated the expression of Bmp2 and Bmp4 genes, and increased the protein level of phospho-Smad1/5/8. Furthermore, TMDQ treatment showed the increased mRNA expression of Wnt ligands, phosphorylation of GSK3, and the expression of β-catenin protein. The TMDQ-induced osteogenic effects were abolished by Wnt inhibitor, Dickkopf-1 (DKK1), and bone morphogenetic protein (BMP) antagonist, noggin. TMDQ-induced runt-related transcription factor 2 (Runx2) expression was attenuatted by noggin and DKK1. These data suggest that TMDQ acts through the activation of BMP, Wnt/β-catenin, and Runx2 signaling to promote osteoblast differentiation, and we demonstrate that TMDQ could be a potential agent for the treatment of bone loss-associated diseases such as osteoporosis.
Background
Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue ...remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma.
Methods
Wild‐type and Chit1‐deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control.
Results
The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF‐β1 were significantly decreased with a diminished number of Foxp3+ regulatory T cells (Treg) in the lungs of Chit1−/− mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF‐β‐stimulated conversion of CD4+CD25− naïve T cells to CD4+Foxp3+ Treg cells, suggesting Chit1 is required for optimal effect of TGF‐β1 in Treg cell differentiation.
Conclusion
Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF‐β expression and Foxp3+ Treg cells.
The demand for spinal fusion surgery has increased over the last decades. Health care providers should take costs and cost-effectiveness of these surgeries into account. Open transforaminal lumbar ...interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF) are two widely used techniques for spinal fusion. Earlier research revealed that TLIF is associated with less blood loss, shorter surgical time and sometimes shorter length of hospital stay, while effectiveness of both techniques on back and/or leg pain are equal. Therefore, TLIF could result in lower costs and be more cost-effective than PLIF. This is the first systematic review comparing direct and indirect (partial) economic evaluations of TLIF with PLIF in adults with lumbar spondylolisthesis. Furthermore, methodological quality of included studies was assessed.
Searches were conducted in eight databases for reporting on eligibility criteria; TLIF or PLIF, lumbar spondylolisthesis or lumbar instability, and cost. Costs were converted to United States Dollars with reference year 2020. Study quality was assessed using the bias assessment tool of the Cochrane Handbook for Systematic Reviews of Interventions, the Level of Evidence guidelines of the Oxford Centre for Evidence-based Medicine and the Consensus Health Economic Criteria (CHEC) list.
Of a total of 693 studies, 16 studies were included. Comparison of TLIF and PLIF could only be made indirectly, since no study compared TLIF and PLIF directly. There was a large heterogeneity in health care and societal perspective costs due to different in-, and exclusion criteria, baseline characteristics and the use of costs or charges in calculations. Health care perspective costs, calculated with hospital costs, ranged from $15,867-$43,217 in TLIF-studies and $32,662 in one PLIF-study. Calculated with hospital charges, it ranged from $8,964-$51,469 in TLIF-studies and $21,838-$93,609 in two PLIF-studies. Societal perspective costs and cost-effectiveness, only mentioned in TLIF-studies, ranged from $5,702/QALY-$48,538/QALY and $50,092/QALY-$90,977/QALY, respectively. Overall quality of studies was low.
This systematic review shows that TLIF and PLIF are expensive techniques. Moreover, firm conclusions about the preferable technique, based on (partial) economic evaluations, cannot be drawn due to limited studies and heterogeneity. Randomized prospective trials and full economical evaluations with direct TLIF and PLIF comparison are needed to obtain high levels of evidence. Furthermore, development of guidelines to perform adequate economic evaluations, specified for the field of interest, will be useful to minimize heterogeneity and maximize transferability of results.
Prospero-database registration number: CRD42020196869.
The mammalian homolog of Drosophila diaphanous (mDia), actin nucleator, has been known to participate in the process of invasion and metastasis of cancer cells via regulating a number of ...actin-related biological processes. We have previously reported that tumor suppressor TIS21(/BTG2/Pc3) (TIS21) inhibits invadopodia formation by downregulating reactive oxygen species (ROS) in MDA-MB-231 cells. We herein report that TIS21(/BTG2/Pc3) downregulates diaphanous-related formin (DRF) expression via reducing NADPH oxidase 4 (Nox4)-derived ROS generation by Akt1 activation and subsequently impairs invasion activity of the highly invasive breast cancer cells. Knockdown of Akt1 by RNA interference recovered the TIS21(/BTG2/Pc3)-inhibited F-actin remodeling and ROS generation by recovering Nox4 expression. Furthermore, Sp1-mediated Nox4 transcription was downregulated by TIS21(/BTG2/Pc3)-Akt1 signals, leading to the inhibition of cancer cell invasion via F-actin remodeling by mDia genes. To our best knowledge, this is the first study to show that TIS21(/BTG2/Pc3)-Akt1 inhibited Sp1-Nox4-ROS cascade, subsequently reducing invasion activity via inhibition of mDia family genes.
The High Resolution Fly's Eye (HiRes) experiment has observed the Greisen-Zatsepin-Kuzmin suppression (called the GZK cutoff) with a statistical significance of five standard deviations. HiRes' ...measurement of the flux of ultrahigh energy cosmic rays shows a sharp suppression at an energy of 6 x 10(19) eV, consistent with the expected cutoff energy. We observe the ankle of the cosmic-ray energy spectrum as well, at an energy of 4 x 10(18) eV. We describe the experiment, data collection, and analysis and estimate the systematic uncertainties. The results are presented and the calculation of the statistical significance of our observation is described.
The present study has developed a numerical simulation tool for the coupled dynamic analysis of multiple turbines on a single floater (or Multiple Unit Floating Offshore Wind Turbine (MUFOWT)) in the ...time domain including multiple-turbine aero-blade-tower dynamics and control, mooring dynamics, and platform motions. The numerical tool developed in this study was designed based on and extended from the single-turbine analysis tool FAST to be suitable for multiple turbines. For hydrodynamic loadings of floating platform and mooring-line dynamics, the CHARM3D program developed by the authors was incorporated. Thus, the coupled dynamic behavior of a floating base with multiple turbines and mooring lines can be simulated in the time domain. The developed MUFOWT analysis tool can compute any type of floating platform with multiple horizontal-axis wind turbines (HAWT). To investigate the dynamic coupling effect between platform and each turbine, one turbine failure case with a fully broken blade was simulated and checked. The aerodynamic interference between adjacent turbines, including wake effect, was not considered in this study to more clearly demonstrate only the dynamic coupling. The analysis shows that some damage-induced excitations from one turbine in MUFOWT may induce appreciable changes in the performance of other turbines or the floating platform.
•We developed the coupled dynamic analysis tool for multiple turbines on a single floater•We demonstrated the performance of three-turbine semi-submersible floater•We examined the dynamic coupling effect between turbines and single floater•One blade broken case was simulated to see the dynamic coupling effect•Complicated coupling effect between multiple turbines and floater can be analyzed by developed tool
Highlights • We evaluate the effects of three prophylactic bolus doses of phenylephrine on spinal hypotension. • Prophylactic bolus injection reduced the incidence of hypotension. • Prophylactic ...bolus of phenylephrine 1.5 μg/kg may be an alternative method to reduce the incidence of hypotension.
Abstract
Aims
Elevated lipoprotein(a) Lp(a) is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating ...monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a).
Methods and results
Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) apo(a) antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (−17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C).
Conclusion
Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).
This review article presents an outlook on the current strategies and existing concepts for culture surface designs to regulate cell morphologies and functions. First, cell structures and cell ...attachment behaviors are described in relation to the interactions between cells and their surroundings. Next, various surface designs are addressed, with a summary of the current topics of particular interest. The architectural features of substrates can be controlled to facilitate the quest for design principles including material choices and geometric modifications. In addition, various types of biomolecules, such as adhesive elements and growth factors, can be incorporated to regulate cell behaviors, including cell attachment, growth and differentiation. It is possible to manipulate these surface variables to produce desired surface designs for inducing cellular responses. In the latter part of this article, the topics discussed involve dendrimer-immobilized surfaces designed in authors' studies dealing with the
in vitro culture processes of differentiated and undifferentiated cells. This article will offer novel insights into the processing of cells and tissues toward therapeutic applications in regenerative medicine.
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