HucMSCs Delay Muscle Atrophy After Peripheral Nerve Injury Through Exosomes by Repressing Muscle-Specific Ubiquitin Ligases.

Cell therapy based on mesenchymal stem cells (MSCs) alleviate muscle atrophy caused by diabetes and aging; however, the impact of human umbilical cord mesenchymal stem cells on muscle atrophy following nerve injury and the underlying mechanisms remain unclear. In this study, we evaluated the therapeutic efficacy of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (hucMSC-EXOs) for muscle atrophy following nerve injury and identified the underlying molecular mechanisms. Sciatic nerve crush injury in rats and the induction of myotubes in L6 cells were used to determine the ameliorating effect of hucMSCs and hucMSC-EXOs on muscle atrophy. Q-PCR and Western blot analyses were used to measure the expression of muscle-specific ubiquitin ligases Fbxo32 (Atrogin1, MAFbx) and Trim63 (MuRF-1). Dual-luciferase reporter gene experiments were conducted to validate the direct binding of miRNAs to their target genes. Local injection of hucMSCs and hucMSC-EXOs mitigated atrophy in the rat gastrocnemius muscle following sciatic nerve crush injury. In vitro, hucMSC-EXOs alleviated atrophy in L6 myotubes. Mechanistic analysis indicated the upregulation of miR-23b-3p levels in L6 myotubes following hucMSC-EXOs treatment. MiR-23b-3p significantly inhibited the expression of its target genes, Fbxo32 and Trim63, and suppressed myotube atrophy. Notably, an miR-23b-3p inhibitor reversed the inhibitory effect of miR-23b-3p on myotube atrophy in vitro. These results suggest that hucMSCs and their exosomes alleviate muscle atrophy following nerve injury. MiR-23b-3p in exosomes secreted by hucMSCs contributes to this mechanism by inhibiting the muscle-specific ubiquitination ligases Fbxo32 and Trim63.

[Effects of Platelet-Rich Plasma-Derived Exosomes on Proliferation and Migration of Tendon Stem/Progenitor Cell].

Objective To investigate the effects of platelet-rich plasma-derived exosomes (PRP-Exos) on the proliferation and migration of tendon stem/progenitor cell (TSPC).Methods PRP-Exos were extracted through the combination of polymer-based precipitation and ultracentrifugation.The morphology,concentration,and particle size of PRP-Exos were identified by transmission electron microscopy and nanoparticle tracking analysis.The expression levels of surface marker proteins on PRP-Exos and platelet membrane glycoproteins were determined by Western blot analysis.Rat TSPC was extracted and cultured,and the expression of surface marker molecules on TSPC was detected using flow cytometry and immunofluorescence staining.The proliferation of TSPC influenced by PRP-Exos was evaluated using CCK-8 assay and EdU assay.The effect of PRP-Exos on the migration of TSPC was evaluated by cell scratch assay and Transwell assay.Results The extracted PRP-Exos exhibit typical saucer-like structures,with a concentration of 4.9×1011 particles/mL,an average particle size of (132.2±56.8) nm,and surface expression of CD9,CD63 and CD41.The extracted TSPC expressed the CD44 protein.PRP-Exos can be taken up by TSPC,and after co-cultured for 48 h,concentrations of 50 and 100 µg/mL of PRP-Exos significantly promoted the proliferation of TSPC (both P<0.001),with no statistical difference between the two concentrations (P=0.283).Additionally,after co-cultured for 24 h,50 µg/mL of PRP-Exos significantly promoted the migration of TSPC (P<0.001).Conclusion Under in vitro culture conditions,PRP-Exos significantly promote the proliferation and migration of rat TSPC.

PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca2+ Influx.

Aging of mesenchymal stem cells(MSCs) has been widely reported to be strongly associated with aging-related diseases, including osteoporosis (OP). In particular, the beneficial functions of mesenchymal stem cells decline with age, limiting their therapeutic efficacy in age-related bone loss diseases. Therefore, how to improve mesenchymal stem cell aging to treat age-related bone loss is the current research focus. However, the underlying mechanism remains unclear. In this study, protein phosphatase 3, regulatory subunit B, alpha isoform, calcineurin B, type I (PPP3R1) was found to accelerate the senescence of mesenchymal stem cells, resulting in reduced osteogenic differentiation and enhanced adipogenic differentiation in vitro. Mechanistically, PPP3R1 induces changes in membrane potential to promote cellular senescence by polarizing to depolarizing, increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. In conclusion, the results identify a novel pathway of mesenchymal stem cell aging that may lead to novel therapeutic approaches for age-related bone loss.

[Human Platelet-Rich Plasma-Derived Exosomes Promote the Proliferation of Schwann Cells Cultured in Vitro].

Objective To investigate the effect of human platelet-rich plasma-derived exosomes(PRP-exos)on the proliferation of Schwann cell(SC)cultured in vitro. Methods PRP-exos were extracted by polymerization-precipitation combined with ultracentrifugation.The morphology of PRP-exos was observed by transmission electron microscopy,and the concentration and particle size distribution of PRP-exos were determined by nanoparticle tracking analysis.Western blotting was employed to determine the expression of the marker proteins CD63,CD81,and CD9 on exosome surface and the platelet membrane glycoprotein CD41.The SCs of rats were isolated and cultured,and the expression of the SC marker S100ß was detected by immunofluorescence staining.The fluorescently labeled PRP-exos were co-cultured with SCs in vitro for observation of their interaction.EdU assay was employed to detect the effect of PRP-exos on SC proliferation,and CCK-8 assay to detect the effects of PRP-exos at different concentrations(0,10,20,40,80,and 160 µg/ml)on SC proliferation. Results The extracted PRP-exos appeared as uniform saucer-shaped vesicles with the average particle size of(122.8±38.7)nm and the concentration of 3.5×1012 particles/ml.CD63,CD81,CD9,and CD41 were highly expressed on PRP-exos surface(P<0.001,P=0.025,P=0.004,and P=0.032).The isolated SCs expressed S100ß,and PRP-exos could be taken up by SCs.PRP-exos of 40,80,and 160 µg/ml promoted the proliferation of SCs,and that of 40 µg/ml showed the best performance(all P<0.01). Conclusions High concentrations of PRP-exos can be extracted from PRP.PRP-exos can be taken up by SCs and promote the proliferation of SCs cultured in vitro.

Activating Wnt/ß-Catenin Signaling in Osteocytes Promotes Osteogenic Differentiation of BMSCs through BMP-7.

Bone formation is critically needed in orthopedic clinical practice. We found that, bone morphogenetic protein-7 (BMP-7) gene expression was significantly increased in fractured mice, which activates canonical Wnt signaling exclusively in osteocytes. Wnt and BMP signaling appear to exhibit synergistic or antagonistic effects in different kinds of cells. However, the communication between Wnt/ß-catenin signaling and BMP signaling in osteocytes is almost unknown. Our study verified in vitro that BMP-7 expression was significantly increased when Wnt signaling was activated in osteocytes. Next, BMP-7 in osteocytes was overexpressed using an adenovirus, the osteogenesis of bone marrow stem cells (BMSCs) was enhanced, when cocultured with osteocytes. On the contrary, BMP-7 in osteocytes was silenced using an adenovirus, the osteogenesis of bone marrow stem cells (BMSCs) was weakened. In addition, the osteogenesis of BMSCs was no longer promoted by Wnt-activated osteocytes when BMP-7 was silenced. Therefore, the results showed that BMP-7 mediated the anabolic actions of Wnt/ß-catenin signaling in osteocytes. Our study provides new evidence for the clinical application of BMP-7-overexpressed osteocytes.

Vertical Charge Transport via Small Polaron Hopping within TIPS-Pentacene Lamellar Single Crystal.

A modified liquid method is employed to grow an ultralarge 6,13-bis(triisopropylsilylethynyl)pentacene crystal, ensuring fabrication and measurements of the two terminal devices. The hole transport mechanism is studied by analyzing the space charge limited currents (SCLCs) at various temperatures. Modified SCLC theory with a small polaron hopping model is developed and employed to successfully simulate the I-V curves. Values of effective hopping distance, transfer integral, and reorganization energy are extracted and reasonably discussed. A scenario is suggested that hopping transport takes place from one molecule to its nearest neighbor along the c-axis, with every molecule acting as a trapping center.

Progress on the relationship between miR-125 family and tumorigenesis.

miRNA-125 family, which is a highly conserved miRNA family throughout evolution, is consist of miRNA-125a-3p, miRNA-125a-5p, miRNA-125b-1 and miRNA-125b-2.The aberrant expression of miR-125 familyis tightly related to tumorigenesis and tumor development. The downstream targets of miRNA-125 include transcription factors like STAT3, cytokines like IL-6 and TGF-ß, tumor suppressing protein p53, pro-apoptotic protein Bak1 and RNA binding protein HuR et al. Through regulating these downstream targets miR-125 family is involved in regulating tumorigenesis and tumor development. Nowadays, miR-125b have already became a putative and valuable biomarker for cancer diagnosis, treatment and prognosis. In this review, we mainly summarize the dual function of miRNA-125 family in suppression and promotion of cancer cells and further elaborate its regulatory mechanisms from four facets, proliferation, apoptosis, invasion or metastasis and immune response.

BN-Enabled Epitaxy of Pb(1-x)Sn(x)Se Nanoplates on SiO2/Si for High-Performance Mid-Infrared Detection.

By designing a few-layer boron nitried (BN) buffer layer, topological crystalline insulator Pb(1-x)Sn(x)Se nanoplates are directly grown on SiO2/Si, which shows high compatibility with current Si-based integrated circuit technology. Back-gated field-effect transistors of Pb(1-x)Sn(x)Se nanoplates exhibit a room-temperature carrier mobility of 0.73-4.90 cm(2) V(-1) s(-1), comparable to layered materials and molecular crystals, and high-efficiency mid-IR detection (1.9-2.0 µm).

miR-92a family and their target genes in tumorigenesis and metastasis.

The miR-92a family, including miR-25, miR-92a-1, miR-92a-2 and miR-363, arises from three different paralog clusters miR-17-92, miR-106a-363, and miR-106b-25 that are highly conservative in the process of evolution, and it was thought as a group of microRNAs (miRNAs) correlated with endothelial cells. Aberrant expression of miR-92a family was detected in multiple cancers, and the disturbance of miR-92a family was related with tumorigenesis and tumor development. In this review, the progress on the relationship between miR-92a family and their target genes and malignant tumors will be summarized.

miR-128 and its target genes in tumorigenesis and metastasis.

MicroRNAs (miRNAs) are a class of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that could modulate gene expression at post-transcriptional level. Previous studies have shown that miR-128 enriched in the brain plays an important role in the development of nervous system and the maintenance of normal physical functions. Aberrant expression of miR-128 has been detected in many types of human tumors and its validated target genes are involved in cancer-related biological processes such as cell proliferation, differentiation and apoptosis. In this review, we will summarize the roles of miR-128 and its target genes in tumorigenesis and metastasis.

A prospective study of two-dimensional ultrasonography combined with shear wave elastography for pregnancy-related diastasis recti abdominis.

Objectives: To compare the inter-rectus distance (IRD), rectus abdominis thickness (RAT), and stiffness in women during pregnancy and postpartum and identify the risk and protective factors affecting diastasis recti abdominis (DRA). Materials and methods: A total of 171 pregnant women who volunteered to participate in this study were recruited. Using an ultrasonographic diagnostic instrument with shear wave elastography function, IRD, RAT and the Young's modulus of the rectus abdominis muscles were measured at 12 weeks, 37 weeks of pregnancy, and 6 weeks postpartum. Results: The IRD at 37 weeks was significantly higher than that at 12 weeks and then decreased at 6 weeks postpartum, but it was still higher than that at 12 weeks (p < 0.001). RAT and Young's modulus decreased significantly at 37 weeks compared with those at 12 weeks and then recovered at 6 weeks postpartum, but they were lower than those at 12 weeks (p < 0.001). IRD at 12 weeks was significantly higher in multiparae than in primiparae (p < 0.001). Moreover, positive correlation between the RAT and Young's modulus of rectus abdominis muscles at 12 and 37 weeks of gestation and 6 weeks postpartum (p < 0.001) was observed. Multiple linear regression analysis showed that the regression equation was significant (f = 24.856, p < 001). Conclusion: Our study identified differences in IRD, thickness and stiffness of the rectus abdominis muscle between early and advanced pregnancy and the postpartum period. The risk and protective factors of DRA may guide pregnant women's protection and treatment.

Harnessing three-dimensional porous chitosan microsphere embedded with adipose-derived stem cells to promote nerve regeneration.

BACKGROUND: Nerve guide conduits are a promising strategy for reconstructing peripheral nerve defects. Improving the survival rate of seed cells in nerve conduits is still a challenge and microcarriers are an excellent three-dimensional (3D) culture scaffold. Here, we investigate the effect of the 3D culture of microcarriers on the biological characteristics of adipose mesenchymal stem cells (ADSCs) and to evaluate the efficacy of chitosan nerve conduits filled with microcarriers loaded with ADSCs in repairing nerve defects. METHODS: In vitro, we prepared porous chitosan microspheres by a modified emulsion cross-linking method for loading ADSCs and evaluated the growth status and function of ADSCs. In vivo, ADSCs-loaded microcarriers were injected into chitosan nerve conduits to repair a 12 mm sciatic nerve defect in rats. RESULTS: Compared to the conventional two-dimensional (2D) culture, the prepared microcarriers were more conducive to the proliferation, migration, and secretion of trophic factors of ADSCs. In addition, gait analysis, neuro-electrophysiology, and histological evaluation of nerves and muscles showed that the ADSC microcarrier-loaded nerve conduits were more effective in improving nerve regeneration. CONCLUSIONS: The ADSCs-loaded chitosan porous microcarrier prepared in this study has a high cell engraftment rate and good potential for peripheral nerve repair.

In-situ gelation of fibrin gel encapsulating platelet-rich plasma-derived exosomes promotes rotator cuff healing.

Although platelet-rich plasma-derived exosomes (PRP-Exos) hold significant repair potential, their efficacy in treating rotator cuff tear (RCT) remains unknown. In light of the potential for clinical translation of fibrin gel and PRP-Exos, we evaluated their combined impact on RCT healing and explored suitable gel implantation techniques. In vitro experiments demonstrated that PRP-Exos effectively enhanced key phenotypes changes in tendon stem/progenitor cells. Multi-modality imaging, including conventional ultrasound, shear wave elastography ultrasound, and micro-computed tomography, and histopathological assessments were performed to collectively evaluate the regenerative effects on RCT. The regenerated tendons exhibited a well-ordered structure, while bone and cartilage regeneration were significantly improved. PRP-Exos participated in the healing process of RCT. In-situ gelation of fibrin gel-encapsulated PRP-Exos at the bone-tendon interface during surgery proved to be a feasible gel implantation method that benefits the healing outcome. Comprehensive multi-modality postoperative evaluations were necessary, providing a reliable foundation for post-injury repair.

Platelet-rich plasma-derived exosomes boost mesenchymal stem cells to promote peripheral nerve regeneration.

Peripheral nerve injury (PNI) remains a severe clinical problem with debilitating consequences. Mesenchymal stem cell (MSC)-based therapy is promising, but the problems of poor engraftment and insufficient neurotrophic effects need to be overcome. Herein, we isolated platelet-rich plasma-derived exosomes (PRP-Exos), which contain abundant bioactive molecules, and investigated their potential to increase the regenerative capacity of MSCs. We observed that PRP-Exos significantly increased MSC proliferation, viability, and mobility, decreased MSC apoptosis under stress, maintained MSC stemness, and attenuated MSC senescence. In vivo, PRP-Exo-treated MSCs (pExo-MSCs) exhibited an increased retention rate and heightened therapeutic efficacy, as indicated by increased axonal regeneration, remyelination, and recovery of neurological function in a PNI model. In vitro, pExo-MSCs coculture promoted Schwann cell proliferation and dorsal root ganglion axon growth. Moreover, the increased neurotrophic behaviour of pExo-MSCs was mediated by trophic factors, particularly glia-derived neurotrophic factor (GDNF), and PRP-Exos activated the PI3K/Akt signalling pathway in MSCs, leading to the observed phenotypes. These findings demonstrate that PRP-Exos may be novel agents for increasing the ability of MSCs to promote neural repair and regeneration in patients with PNI.

Sustained release of a highly specific GSK3ß inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis.

The safe and effective use of Wnt signaling is a hot topic in developing osteogenic drugs. SB216763 (S33) is a widely used highly specific GSK3ß inhibitor. Here, we show that S33 initiates canonical Wnt signaling by inhibiting GSK3ß activity in the bone marrow stromal cell line ST2 and increases osteoblast marker alkaline phosphatase activity, osteoblast marker gene expression including Alpl, Col1α1, and Runx2, promoting osteogenic differentiation and mineralization of ST2 cells. In addition, S33 suppressed the expression of adipogenic transcription factors Pparg and Cebpa in ST2 cells to suppress adipogenesis. ICRT-14, a specific transcriptional inhibitor of Wnt signaling, reversed the effects of S33 on the differentiation of ST2 cells. S33 also increased the expression of osteoclast cytokines RANKL and Opg but decreased the RANKL/Opg ratio and had the potential to inhibit osteoclast differentiation. In addition, we printed the PSCI3D (polycaprolactone, S33, cell-integrated 3D) scaffolds using a newly established integrated 3D printing system for hard materials and cells. S33 sustained release in the hydrogel of the scaffold with 25.4% release on day 1% and 81.7% release over 7 days. Cells in the scaffolds had good cell viability. The ratio of live/dead cells remained above 94% for 7 days, while the cells in the scaffolds proliferated linearly, and the proliferative activity of the PSCI3D scaffold group increased 1.4-fold and 1.7-fold on days 4 and 7, respectively. Similarly, in PSCI3D scaffolds, osteogenic differentiation of st2 cells was increased. The alkaline phosphatase activity increased 1.4- and 4.0-fold on days 7 and 14, respectively, and mineralization increased 1.7-fold at 21 days. In addition, PSCI3D conditioned medium promoted migration and tubulogenesis of HUVECs, and S33 upregulated the expression of Vegfa, a key factor in angiogenesis. In conclusion, our study suggests that S33 functions in osteogenesis, anti-adipogenesis, and potential inhibition of osteoclast differentiation. And the sustained release of S33 in PSCI3D scaffolds creates a safe osteogenic niche, which promotes cell proliferation, osteogenesis, and angiogenesis and has application prospects.

Ultrasound-Targeted Microbubble Destruction Assisted Delivery of Platelet-Rich Plasma-Derived Exosomes Promoting Peripheral Nerve Regeneration.

Peripheral nerve injury is prevalent and has a high disability rate in clinical settings. Current therapeutic methods have not achieved satisfactory efficacy, underscoring the need for novel approaches to nerve restoration that remains an active area of research in neuroscience and regenerative medicine. In this study, we isolated platelet-rich plasma-derived exosomes (PRP-exos) and found that they can significantly enhance the proliferation, migration, and secretion of trophic factors by Schwann cells (SCs). In addition, there were marked changes in transcriptional and expression profiles of SCs, particularly via the upregulation of genes related to biological functions involved in nerve regeneration and repair. In the rat model of sciatic nerve crush injury, ultrasound-targeted microbubble destruction (UTMD) enhanced the efficiency of PRP-exos delivery to the injury site. This approach ensured a high concentration of PRP-exos in the injured nerve and improved the therapeutic outcomes. In conclusion, PRP-exos may promote nerve regeneration and repair, and UTMD may increase the effectiveness of targeted PRP-exos delivery to the injured nerve and enhance the therapeutic effect.

Circular RNA circSP3 promotes hepatocellular carcinoma growth by sponging microRNA-198 and upregulating cyclin-dependent kinase 4.

As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs), have been found to influence cell development and function by sponging microRNAs. MicroRNA (miR)-198 is downregulated in various cancers, including hepatocellular carcinoma (HCC). We therefore searched for dysregulated circRNAs that could sponge miR-198 in HCC. By analyzing relevant circRNA databases (circBase, TargetScan and CircInteractome), we found that the miR-198-binding circRNA hsa_circSP3 is upregulated in HCC. CircSP3 expression correlated negatively with miR-198 expression in HCC tissues. Dual luciferase reporter assays indicated that circSP3 bound to miR-198. CircSP3 overexpression in HCC cells induced expression of cyclin-dependent kinase 4, a target gene of miR-198. Silencing circSP3 inhibited HCC cell proliferation and migration by downregulating cyclin-dependent kinase 4, whereas inhibiting miR-198 reversed those effects. In vivo experiments confirmed that circSP3 promoted xenograft tumor growth. These data suggest that circSP3 may be a novel biomarker for HCC.

Hotspot and Frontier Analysis of Exercise Training Therapy for Heart Failure Complicated With Depression Based on Web of Science Database and Big Data Analysis.

Background: Exercise training has been extensively studied in heart failure (HF) and psychological disorders, which has been shown to worsen each other. However, our understanding of how exercise simultaneously protect heart and brain of HF patients is still in its infancy. The purpose of this study was to take advantage of big data techniques to explore hotspots and frontiers of mechanisms that protect the heart and brain simultaneously through exercise training. Methods: We studied the scientific publications on related research between January 1, 2003 to December 31, 2020 from the WoS Core Collection. Research hotspots were assessed through open-source software, CiteSpace, Pajek, and VOSviewer. Big data analysis and visualization were carried out using R, Cytoscape and Origin. Results: From 2003 to 2020, the study on HF, depression, and exercise simultaneously was the lowest of all research sequences (two-way ANOVAs, p < 0.0001). Its linear regression coefficient r was 0.7641. The result of hotspot analysis of related keyword-driven research showed that inflammation and stress (including oxidative stress) were the common mechanisms. Through the further analyses, we noted that inflammation, stress, oxidative stress, apoptosis, reactive oxygen species, cell death, and the mechanisms related to mitochondrial biogenesis/homeostasis, could be regarded as the primary mechanism targets to study the simultaneous intervention of exercise on the heart and brain of HF patients with depression. Conclusions: Our findings demonstrate the potential mechanism targets by which exercise interferes with both the heart and brain for HF patients with depression. We hope that they can boost the attention of other researchers and clinicians, and open up new avenues for designing more novel potential drugs to block heart-brain axis vicious circle.

miR-26 family and its target genes in tumorigenesis and development.

The microRNA-26 family, including miR-26a, miR-26b, miR-1297 and miR-4465, is a group of broadly conserved small RNAs with identical sequences at the seed region. The expression of miR-26 could be induced by hypoxia via a HIF-dependent mechanism, and up-regulated during multiple cell differentiation. Accumulating studies have demonstrated that miR-26 family members could be detected in many different kinds of tumors, and their validated target genes are involved in cell metabolism, proliferation, differentiation, apoptosis, invasion and metastasis. The expression of miR-26 might be a potentially valuable biomarker and a new target for cancer therapy. In this review, miR-26 family and its target genes in tumorigenesis and development will be summarized as follows.

(E)-4-Bromo-N'-(2-chloro-benzyl-idene)benzohydrazide.

In the title compound, C(14)H(10)BrClN(2)O, the dihedral angle between the two benzene rings is 11.4 (2)°. In the crystal structure, mol-ecules are connected via inter-molecular N-H⋯O hydrogen bonds into one-dimensional chains running parallel to the c axis.