Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis

<div><p>Background</p><p>Preclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence.</p><p>Methods</p><p>Pubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes.</p><p>Results</p><p>Pooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, <i>P</i> < 0.001) with moderate heterogeneity (Cochrane’s Q test: <i>P</i> = 0.02, I² = 45%) among the constituent studies. Implantation of bone marrow cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, and human umbilical cord blood-derived CD34+ cells, were all associated with improved BMD as compared to that in the controls (<i>P</i> < 0.05 for all); the only exception being the use of embryonic stem cell transplantation (<i>P</i> > 0.05). Egger’s test detected potential publication bias (<i>P</i> = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, <i>P</i> < 0.001).</p><p>Conclusions</p><p>Stem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies.</p></div

Flow diagram illustrating the study selection criteria for the meta-analysis.

<p><i>BMD</i>, <i>Bone mineral density</i></p

Forest plot of the meta-analysis of standardized mean difference of bone mineral density by study group (stem cell based treatment- vs. control group).

<p><i>BMD, Bone mineral density</i>; <i>SD, standard deviation; CI, confidence interval; df, degrees of freedom</i></p

Quality assessment of studies included in the meta-analysis using the modified Jadad Score.

<p>Quality assessment of studies included in the meta-analysis using the modified Jadad Score.</p

Multiplex Iterative Plasmid Engineering for Combinatorial Optimization of Metabolic Pathways and Diversification of Protein Coding Sequences

Engineering complex biological systems typically requires combinatorial optimization to achieve the desired functionality. Here, we present Multiplex Iterative Plasmid Engineering (MIPE), which is a highly efficient and customized method for combinatorial diversification of plasmid sequences. MIPE exploits ssDNA mediated λ Red recombineering for the introduction of mutations, allowing it to target several sites simultaneously and generate libraries of up to 10⁷ sequences in one reaction. We also describe “restriction digestion mediated co-selection (RD CoS)”, which enables MIPE to produce enhanced recombineering efficiencies with greatly simplified coselection procedures. To demonstrate this approach, we applied MIPE to fine-tune gene expression level in the 5-gene riboflavin biosynthetic pathway and successfully isolated a clone with 2.67-fold improved production in less than a week. We further demonstrated the ability of MIPE for highly multiplexed diversification of protein coding sequence by simultaneously targeting 23 codons scattered along the 750 bp sequence. We anticipate this method to benefit the optimization of diverse biological systems in synthetic biology and metabolic engineering

Baseline characteristics of the studies included in the meta-analysis.

<p>Baseline characteristics of the studies included in the meta-analysis.</p

Funnel plot using ‘trim and fill’ method for meta-analysis of standardized mean difference (SMD) of bone mineral density for animals assigned to the stem cell based treatment and the control groups.

<p>The unfilled data points represent the identified studies included in the meta-analysis, and the black dots represent the imputed missing studies after adjustment for publication bias. <i>s</i>.<i>e</i>. <i>of SMD; standard error of the standardized mean difference</i></p

Butylphthalide improves brain damage induced by renal ischemia-reperfusion injury rats through Nrf2/HO-1 and NOD2/MAPK/NF-κB pathways

Renal ischemia-reperfusion (I/R) injury leads to irreversible brain damage with serious consequences. Activation of oxidative stress and release of inflammatory mediators are considered potential pathological mechanisms. Butylphthalide (NBP) has anti-inflammatory and antioxidant effects on I/R injuries. However, it is unclear whether NBP can effectively mitigate renal I/R secondary to brain injury as well as its mechanism, which are the aims of this study. Both renal I/R injury rats and oxygen and glucose deprivation cell models were established and pre-intervened NBP. The Morris water maze assay was used to detect behavior. Hippocampal histopathology and function were examined after renal I/R. Apoptosis and tube-forming capacity of brain microvascular endothelial cells (BMVECs) were tested. Immunohistochemistry and Western blot were used to measure protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) pathway and NOD-like receptor C2 (NOD2)/Mitogen-activated protein kinases (MAPK)/Nuclear factor kappa-B (NF-κB) pathway. NBP treatment attenuated renal I/R-induced brain tissue damage and learning and memory dysfunction. NBP treatment inhibited apoptosis and promoted blood-brain barrier restoration and microangiogenesis. Also, it decreased oxidative stress levels and pro-inflammatory factor expression in renal I/R rats. Furthermore, NBP enhanced BMVECs’ viability and tube-forming capacity while inhibiting apoptosis and oxidative stress. Notably, the alleviating effects of NBP were attributed to Nrf2/HO-1 pathway activation and NOD2/MAPK/NF-κB inhibition. This study demonstrates that NBP maintains BBB function by activating the Nrf2/HO-1 pathway and inhibiting the NOD2/MAPK/NF-κB pathway to suppress inflammation and oxidative stress, thereby alleviating renal I/R-induced brain injury.</p

Toward the Next-Generation Nanomedicines: Design of Multifunctional Multiblock Polyurethanes for Effective Cancer Treatment

Specific accumulation of therapeutics at tumor sites to improve <i>in vivo</i> biodistribution and therapeutic efficacy of anticancer drugs is a major challenge for cancer therapy. Herein, we demonstrate a new generation of intelligent nanosystem integrating multiple functionalities in a single carrier based on multifunctional multiblock polyurethane (MMPU). The smart nanocarriers equipped with stealth, active targeting, and internalizable properties can ferry paclitaxel selectively into tumor tissue, rapidly enter cancer cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in an improved biodistribution and excellent antitumor activity <i>in vivo</i>. Our work provides a facile and versatile approach for the design and fabrication of smart intracellular targeted nanovehicles for effective cancer treatment, and opens a new era in the development of biodegradable polyurethanes for next-generation nanodelivery systems

Alkoxy Substitution on Asymmetric Conjugated Molecule Enabling over 18% Efficiency in Ternary Organic Solar Cells by Reducing Nonradiative Voltage Loss

A ternary strategy is considered to be an efficient and simple way to further enhance the performance of organic photovoltaics (OPVs). However, the “structure–performance” correlation of the third component in the ternary device has rarely been clearly understood from the aspect of the material’s eigenproperties. Herein, this relationship is investigated in depth by employing three asymmetric skeleton nonfullerene acceptors as the third component in the host system of PM6:BTP-eC9, respectively. Compared with TB-S and TB-S1, the alkoxy-substituted TB-S1-O possesses a more stable planar conformation, a higher surface energy, and a larger ordered stacking domain due to the existence of noncovalent conformational locking (O···H). Consequently, the PM6:BTP-eC9:TB-S1-O device exhibits the highest efficiency of 18.14% as compared with the devices based on PM6:BTP-eC9:TB-S (16.16%) and PM6:BTP-eC9:TB-S1 (16.18%). Most interestingly, only the PM6:BTP-eC9:TB-S1-O device can maintain the positive effect of VOC improvement, because a significant reduction in nonradiative voltage loss can be observed in this device. Our systematic study reveals that alkoxy substitution on an asymmetric backbone is an efficient method to construct the third component for high-performance ternary organic solar cells