Repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in cynomolgus monkeys by intravenous and subcutaneous injection.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) are proposed for the treatment of acute lung injury and atopic dermatitis. To advance hUC-MSC entry into clinical trials, the effects of hUC-MSCs on the general toxicity, immune perturbation and toxicokinetic study of hUC-MSCs in cynomolgus monkeys were assessed. hUC-MSCs were administered to cynomolgus monkeys by intravenous infusion of 3.0 × 106 or 3.0 × 107cells/kg or by subcutaneous injection of 3.0 × 107cells/kg twice a week for 3 weeks followed by withdrawal and observation for 6 weeks. Toxicity was assessed by clinical observation, clinical pathology, ophthalmology, immunotoxicology and histopathology. Moreover, toxicokinetic study was performed using a validated qPCR method after the first and last dose. After 3rd or 4th dosing, one or three the monkeys in the intravenous high-dose group exhibited transient coma, which was eliminated by slow-speed infusion after 5th or 6th dosing. In all dose groups, hUC-MSCs significantly increased NEUT levels and decreased LYMPH and CD3+ levels, which are related to the immunosuppressive effect of hUC-MSCs. Subcutaneous nodules and granulomatous foci were found at the site of administration in all monkeys in the subcutaneous injection group. Other than above abnormalities, no obvious systemic toxicity was observed in any group. The hUC-MSCs was detectable in blood only within 1 h after intravenous and subcutaneous administration. The present study declared the preliminary safety of hUC-MSCs, but close monitoring of hUC-MSCs for adverse effects, such as coma induced by intravenous infusion, is warranted in future clinical trials.

A repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in NOG mice by intravenous injection.

BACKGROUND: Stem cell-based therapies have demonstrated great potential in several clinical trials. However, safety data on stem cell application remain inadequate. This study evaluated the toxicity of human umbilical cord mesenchymal stem cells (hUC-MSCs) in NOD/Shi-scid/IL-2 Rγnull (NOG) mice. RESEARCH DESIGN AND METHODS: Mice were administered hUC-MSCs intravenously at doses of 3.5 × 106 cells/kg and 3.5 × 107 cells/kg. Toxicity was assessed by clinical observation, behavioral evaluation, pathology, organ weight, and histopathology. We determined the distribution of hUC-MSCs using a validated qPCR method and colonization using immunohistochemistry. RESULTS: No significant abnormal effects on clinical responses, body weight, or food intake were observed in the mice, except for two in the high-dose group that died during the last administration. Mouse activity in the high-dose group decreased 6 h after the first administration. Terminal examination revealed dose-dependent changes in hematology. The mice in the high-dose group displayed pulmonary artery wall plaques and mild alveolar wall microthrombi. hUC-MSCs colonized primarily the lung tissues and were largely distributed there 24 h after the final administration. CONCLUSIONS: The no observed adverse effect level for intravenous administration of hUC-MSCs in NOG mice over a period of 3 w was 3.5 × 106 cells/kg.

Recent Developments of Gramine: Chemistry and Biological Activity.

The natural alkaloid gramine has attracted significant attention in both academic and industrial circles because of its potential and diverse biological activities, including antiviral, antibacterial, antifungal, anti-inflammatory and antitumor activities; application in therapy for Alzheimer's disease; serotonin-receptor-related activity; insecticidal activity; and application as an algicide. In this review, we focus on the research advances that have been made for gramine-based molecules since their discovery, providing key information on their extraction and separation, chemical synthesis and diverse biological activities. Data regarding their mechanisms of action are also presented. This comprehensive and critical review will serve as a guide for developing more drug candidates based on gramine skeletons.

Classification of multiple cancer types by combination of plasma-based near-infrared spectroscopy analysis and machine learning modeling.

BACKGROUND AND AIM: Near-infrared spectroscopy (NIRS) is a non-invasive and convenient tool, which gains features related to chemical components in biological samples. Machine learning (ML) has been popularized in medical diagnosis. This study aimed at investigating a novel cancer diagnosis strategy using NIRS data based ML modeling. METHODS: Plasma samples were collected from a total of 247 participants, including lung cancer, cervical cancer, nasopharyngeal cancer, and healthy control, and were randomly split into train set and test set. After performing NIRS analysis, the train dataset was utilized to train ML models, including partial least-squares (PLS), random forest (RF), gradient boosting machine (GBM), and support-vector machine (SVM). Subsequently, these models were tested for their prediction performance by the test set. RESULTS: All ML models demonstrated high prediction performance in differentiating cancers from controls, and SVM had high prediction accuracy for different types of cancers. SVM was considered as the most suitable model for its minimal computational cost and high accuracies for both binary and quaternary classification. CONCLUSIONS: This strategy coupling NIRS with ML is insightful that may aid in clinic cancer diagnosis, while further studies should test our results in a larger cohort with better representativeness.

Degree of Soft Tissue Injury is a Major Determinant of Successful Arterial Repair in the Extremity: A New Classification of Extremity Arterial Injury?

BACKGROUND: This study aimed to investigate outcomes after extremity arterial injury repair and examined the association between outcomes and the degree of soft tissue injury and vascular repair methods. METHODS: A retrospective study was conducted on 106 patients (108 cases) who underwent emergent microsurgical repair of extremity arterial injury due to trauma and non-perfusion of the affected extremity. The cases were divided into three groups by degree of associated soft tissue injuries: (A) adequate soft tissue coverage over the injured major vessels after radical debridement, (B) inadequate soft tissue coverage over the injured major vessels after radical debridement, and (C) radical debridement was not feasible due to unclear extent of injured soft tissue. Differences in vascular repair methods and outcomes among the three groups were analyzed. RESULTS: In Group A (n = 61), microvascular suture and vessel graft achieved 95.1% and 85.0% successful limb reperfusion, respectively. In Group B (n = 31), vessel reconstruction with flap coverage achieved 100% successful reperfusion. Vessel graft achieved 28.6% successful limb reperfusion, while there were no cases of successful reperfusion using microvascular sutures. In Group C (n = 16), no vascular repair method achieved successful reperfusion. There were significant differences among the three groups in successful reperfusion (p < 0.001) and limb salvage (p < 0.001). CONCLUSION: The extent of associated soft tissue injury was associated with different vascular repair methods and outcomes. We propose a new system for classifying these injuries according to the degree of associated soft tissue injury.

Site of Nerve Division Affects Pain-Related Behavior and Spinal Cord Glial Proliferation after C7 Neurotomy in a Rat Stroke Model.

Objective: This study aimed to evaluate whether the site of C7 neurotomy affects spinal cord glial cell activation and pain-related behavior on the paralyzed side in a rat stroke model. Methods: After middle cerebral artery occlusion (MCAO) was induced in male Sprague-Dawley rats, they underwent C7 neurotomy 0, 2, and 4 mm distal to the intervertebral foramen on the paralyzed side. Pain-related behavior and immunofluorescence examination of spinal cord glial cell activation in the ipsilateral C7 dorsal horn were evaluated. Results: Mechanical paw withdrawal threshold (MPWT) was lower, and the number of microglia and astrocytes (/mm2) was higher as the distance between the site of C7 neurotomy and the intervertebral foramen decreased from 4 mm to 0. Conclusion: The site of C7 neurotomy affects MPWT and spinal cord glial proliferation in rats with MCAO. Nerve division closer to intervertebral foramen resulted in lower MPWT and higher degree of glial proliferation in the spinal cord.

DNAzyme-based biosensors for mercury (â ¡) detection: Rational construction, advances and perspectives.

Mercury contamination is one of the most severe issues in society due to its threats to public health and the ecological system. However, traditional methods for mercury ion detection are still limited by their time-consuming procedures, requirement of expensive instruments, and low selectivity. In recent decades, tremendous progress has been made in the development of functional nucleic acid-based, especially DNAzyme sensors for mercury (Ⅱ) (Hg2+) determination, including RNA-cleaving DNAzymes and G-quadruplex-based DNAzymes in particular. Researchers have heavily studied the construction of Hg2+ sensors, mainly originating from in vitro selection-derived DNAzymes, by incorporating T-Hg2+-T recognition moieties in existing DNAzyme scaffolds, and interfacing Hg2+-sensitive sequences with nanomaterials. In the last case, the employment of materials (as quenchers, signal transducers and DNA immobilizers) enriches the application scenarios of current Hg2+-DNAzymes, due to a combination of their functions. We summarize a broad range of sensing approaches, including optical, electrochemical, and other sensing methods, and compare their features. This review elaborates on the rational design strategies for engineering DNAzymes to selectively sense Hg2+, critically discusses their properties in different application scenarios, and summarizes recent advances in this field. Additionally, current progress, challenges and future perspectives are also discussed. This minireview provides deeper insights into the chemistry of these functional nucleic acids when working with Hg2+, explains the design ideas of DNAzyme-sensors in each platform, and reveals potential opportunities in developing more advanced DNAzyme sensors for the highly selective and sensitive recognition of Hg2+. ENVIRONMENTAL IMPLICATION: Mercury is one of the most toxic metallic contaminants due to its high toxicity, non-biodegradability, and serious human health risks when accumulated in the body. In the recent decade, intensive studies have focused on exploring mercury sensors by combining DNAzymes with various sensing methods, paving a promising avenue to gain ultra-high sensitivity and selectivity. However, so far, no review has introduced the recent advances on DNAzyme-based sensors for mercury detection in a critical way. In this review, we comprehensively summarized the studies on DNAzyme-based sensors for mercury detection using various sensing techniques including optical, electrochemical and other sensing methods.

Large-scale analyses of heat shock transcription factors and database construction based on whole-genome genes in horticultural and representative plants.

Heat shock transcription factor (Hsf) plays a critical role in regulating heat resistance. Here, 2950 Hsf family genes were identified from 111 horticultural and representative plants. More Hsf genes were detected in higher plants than lower plants. Based on all Hsf genes, we constructed a phylogenetic tree, which indicated that Hsf genes of each branch evolved independently after species differentiation. Furthermore, we uncovered the evolutionary trajectories of Hsf genes by motif analysis. There were only 6 motifs (M1 to M6) in lower plants, and then 4 novel motifs (M7-M10) appeared in higher plants. However, the motifs of some Hsf genes were lost in higher plant, indicating that Hsf genes have undergone sequence variation during the evolution. The number of Hsf gene loss was more than duplication after whole-genome duplication in higher plants. The heat response network was constructed using 24 Hsf genes, 2421 downstream, and 222 upstream genes of Arabidopsis. Further enrichment analysis revealed that Hsf genes and other transcription factors interacted with each other to response heat resistance. The global expression maps were illustrated for Hsf genes under various abiotic, biotic stresses, and several developmental stages in Arabidopsis. The syntenic and phylogenetic analyses were conducted using Hsf genes of Arabidopsis and Pan-genome of 18 Brassica rapa accessions. We also performed the expression pattern analysis of Hsf and six Hsp family genes using expression values from different tissues and heat treatments in B. rapa. The interaction network between Hsf and Hsp gene families was constructed in B. rapa, and several core genes were detected in the network. Finally, we constructed a Hsf database (http://hsfdb.bio2db.com) for researchers to retrieve Hsf gene family information. Therefore, our study will provide rich resources for the evolution and functional study of Hsf genes.

Functional outcome of contralateral C7 nerve transfer combined with free functional gracilis transplantation to repair total brachial plexus avulsion: a report of thirty-nine cases.

PURPOSE: Treatment of total brachial plexus avulsion (TBPA) is a challenge in the clinic, especially the restoration of hand function. The current main surgical order is from proximal to distal joints. The purpose of this study was to demonstrate the outcomes of "distal to proximal" surgical method. METHODS: Thirty-nine patients underwent contralateral C7 (CC7) nerve transfer to directly repair the lower trunk (CC7-LT) and phrenic nerve transfer to the suprascapular nerve (PN-SSN) during the first stage, followed by free functional gracilis transplantation (FFGT) for elbow flexion and finger extension. Muscle strength of upper limb, degree of shoulder abduction and elbow flexion, and Semmes-Weinstein monofilament test and static two-point discrimination of the hand were examined according to the modified British Medical Research Council (mBMRC) scoring system. RESULTS: The results showed that motor recovery reached a level of M3 + or greater in 66.7% of patients for shoulder abduction, 87.2% of patients for elbow flexion, 48.7% of patients for finger extension, and 25.6% of patients for finger flexion. The mean shoulder abduction angle was 45.5° (range 0-90°), and the average elbow flexion angle was 107.2° (range 0-142°), with 2.5 kg average flexion strength (range 0.5-5 kg). In addition, protective sensibility (≥ S2) was found to be achieved in 71.8% of patients. CONCLUSION: In reconstruction of TBPA, CC7 transfer combined with free functional gracilis transplantation is an available treatment method. It could help patients regain shoulder joint stability and the function of elbow flexion and finger extension and, more importantly, provide finger sensation and partial finger flexion function. However, the pick-up function was unsatisfied, which needed additional surgery.

Copper ions assisted fluorescent detection of some dithiocarbamates based on nickel nanocluster with aggregation-induced emission enhancement behavior.

Pesticide residue contamination has become an urgent issue since it threatens both the natural environment and public health. In this study, a fluorescent method for detecting dithiocarbamate (DTC) compounds was constructed based on novel nickel nanoclusters (Ni NCs) and copper ions (Cu2+). The water-soluble fluorescent Ni NCs were synthesized for the first time through a one-pot method using glutathione as stabilizer and ascorbic acid as reducing agent. The as-prepared Ni NCs exhibited a maximum fluorescence emission at 445 nm when excited by 380 nm. And they displayed aggregation-induced emission enhancement when ethylene glycol was introduced into the nanocluster aqueous solution. Based on the Ni NCs, a label-free fluorescence quenching sensor was established for sensitive and selective detection of DTC compounds with the assistance of Cu2+. The complex formed by DTC and Cu2+ led to fluorescence quenching of Ni NCs through inner filter effect. The sensing method was successfully applied to two typical DTC compounds, thiram and disulfiram, with good linearity over a wide linear range and a low detection limit. Moreover, the proposed approach was capable of thiram detection in real samples, which confirms the potential of this sensing method as a platform for DTC compound detection.

Electrochemical detection of methyl-paraoxon based on bifunctional cerium oxide nanozyme with catalytic activity and signal amplification effect.

A new electrochemical sensor for organophosphate pesticide (methyl-paraoxon) detection based on bifunctional cerium oxide (CeO2) nanozyme is here reported for the first time. Methyl-paraoxon was degraded into p-nitrophenol by using CeO2 with phosphatase mimicking activity. The CeO2 nanozyme-modified electrode was then synthesized to detect p-nitrophenol. Cyclic voltammetry was applied to investigate the electrochemical behavior of the modified electrode, which indicates that the signal enhancement effect may attribute to the coating of CeO2 nanozyme. The current research also studied and discussed the main parameters affecting the analytical signal, including accumulation potential, accumulation time, and pH. Under the optimum conditions, the present method provided a wider linear range from 0.1 to 100 µmol/L for methyl-paraoxon with a detection limit of 0.06 µmol/L. To validate the proof of concept, the electrochemical sensor was then successfully applied for the determination of methyl-paraoxon in three herb samples, i.e., Coix lacryma-jobi, Adenophora stricta and Semen nelumbinis. Our findings may provide new insights into the application of bifunctional nanozyme in electrochemical detection of organophosphorus pesticide.

The Fecal Microbiota Transplantation: A Remarkable Clinical Therapy for Slow Transit Constipation in Future.

Slow transit constipation is a common condition that would be difficult to treat in clinical practice with a widespread incidence in the population. Pharmacotherapy and surgery are common treatment modalities. However, the clinical effect is limited, and patients still suffer from it. As the researchers strived in this field for decades, the profound relationship between slow transit constipation and fecal microbiota transplantation has comprehensively been sustained. It is very pivotal to maintain intestinal homeostasis, the structure function and metabolic function of symbiotic bacteria, which can inhibit the engraftment of intestinal pathogens. This mini review explains the treatment effects and possible mechanisms of the fecal microbiota transplantation in treating slow transit constipation. Simultaneously, it is found that there is significant improvement in the disease by adjusting the intestinal microbes like fecal microbiota transplantation. Fecal microbiota transplantation has efficient therapeutic effects in slow transit constipation compared with traditional therapies.

Evidences for the mechanism of Shenmai injection antagonizing doxorubicin-induced cardiotoxicity.

BACKGROUND: Doxorubicin (DOX) is a widely used antitumor drug. However, its clinical application is limited for its serious cardiotoxicity. The mechanism of DOX-induced cardiotoxicity is attributed to the increasing of cell stress in cardiomyocytes, then following autophagic and apoptotic responses. Our previous studies have demonstrated the protective effect of Shenmai injection (SMI) on DOX-induced cardiotoxicity via regulation of inflammatory mediators for releasing cell stress. PURPOSE: To further investigate whether SMI attenuates the DOX-induced cell stress in cardiomyocytes, we explored the mechanism underlying cell stress as related to Jun N-terminal kinase (JNK) activity and the regulation of autophagic flux to determine the mechanism by which SMI antagonizes DOX-induced cardiotoxicity. STUDY DESIGN: The DOX-induced cardiotoxicity model of autophagic cell death was established in vitro to disclose the protected effects of SMI on oxidative stress, autophagic flux and JNK signaling pathway. Then the autophagic mechanism of SMI antagonizing DOX cardiotoxicity was validated in vivo. RESULTS: SMI was able to reduce the DOX-induced cardiomyocyte apoptosis associated with inhibition of activation of the JNK pathway and the accumulation of reactive oxygen species (ROS). Besides, SMI antagonized DOX cardiotoxicity, regulated cardiomyocytes homeostasis by restoring DOX-induced cardiomyocytes autophagy. Under specific circumstances, SMI depressed autophagic process by reducing the Beclin 1-Bcl-2 complex dissociation which was activated by DOX via stimulating the JNK signaling pathway. At the same time, SMI regulated lysosomal pH to restore the autophagic flux which was blocked by DOX in cardiomyocytes. CONCLUSION: SMI regulates cardiomyocytes apoptosis and autophagy by controlling JNK signaling pathway, blocking DOX-induced apoptotic pathway and autophagy formation. SMI was also found to play a key role in restoring autophagic flux for counteracting DOX-damaged cardiomyocyte homeostasis.

LncRNA AGAP2-AS1 Promotes Cancer Cell Proliferation, Migration and Invasion in Colon Cancer by Forming a Negative Feedback Loop with LINC-PINT.

INTRODUCTION: It has been reported that lncRNA AGAP2-AS1 promotes the development of gastric cancer, lung cancer and breast cancer. This study aimed to investigate the role of AGAP2-AS1 in colon cancer. METHODS: A total of 66 patients with colon cancer were enrolled. RT-qPCR was performed to detect the differential expression of AGAP2-AS1 in tumor tissues and adjacent normal tissues. To test the interaction between AGAP2-AS1 and LINC-PINT in colon cancer, overexpression vector or inhibitor of AGAP2-AS1 and LINC-PINT were transfected into RKO and HCT 116 cells. CCK-8 assay was used to detect cell proliferation. Transwell assays were performed to evaluate cell migration and invasion. The expression of p-LATS1, p-YAP and nuclear YAP were detected by Western blot and immunofluorescence. RESULTS: The expression of AGAP2-AS1 was upregulated in colon cancer tissues compared with that in adjacent normal tissues, and the expression of AGAP2-AS1 in colon cancer tissues was not significantly affected by tumor stages. In addition, we found that the expression of LINC-PINT was downregulated in colon cancer tissues compared with that in adjacent normal tissues and had a reverse correlation with the expression of AGAP2-AS1 in colon cancer tissues. Moreover, overexpression of AGAP2-AS1 downregulated the expression of LINC-PINT, and overexpression of LINC-PINT also altered the expression of AGAP2-AS1 in colon cancer cells. Inhibition of AGAP2-AS1 upregulated the expression of LINC-PINT, and inhibition of LINC-PINT promoted the expression levels of AGAP2-AS1 in colon cancer cells. Furthermore, overexpression of AGAP2-AS1 could increase the proliferation, invasion and migration of colon cancer cells, while overexpression of LINC-PINT could attenuate the effects of overexpression of AGAP2-AS1 on the proliferation, migration and invasion of colon cancer cells. We also found that AGAP2-AS1 promoted colon cancer cell proliferation, migration and invasion through the Hippo signaling. CONCLUSION: Upregulated expression of AGAP2-AS1 promoted proliferation, invasion and migration in colon cancer by forming a negative feedback loop with LINC-PINT.

Ultrasonic evaluation of muscle functional recovery following free functioning gracilis transfer, a preliminary study.

BACKGROUND: Ultrasonic measurement has not been utilized to assess the functional recovery of transplanted muscle. This study aimed to investigate the feasibility of using B-ultrasound measurement to assess muscle recovery following free functioning gracilis transfer. METHODS: From January 2009 to January 2014, 35 patients receiving free functioning gracilis transfer to treat total brachial plexus injury were enrolled. B-ultrasound was adopted to determine the cross-sectional area (CSA) of transplanted gracilis muscle at rest and contraction state. The ratio of pre- to post-transplant CSA value at rest state was defined as muscle bulk ratio (MBR). The ratio of CSA value at contraction state to rest state was defined as contraction ratio (CR). RESULTS: Patients with muscle strength M ≥ 4 had significantly higher CR1 (post-transplant), CR2 (pre-transplant), and range of motion (ROM, joint mobility) than those with muscle strength M < 4. The CR1 > CR2 group had significantly higher CR1, muscle strength, and ROM than the CR1 ≤ CR2 group. The MBR > 1 group had significantly higher muscle strength than the MBR ≤ 1 group. CR1 value was highly correlated with muscle strength and with ROM. CR2 value was moderately correlated with muscle strength and ROM. Multivariate linear regression analysis showed that a higher CR1/CR2 value was associated with a higher muscle strength and joint mobility. The CR1 > CR2 group had better muscle strength and ROM than the CR1 ≤ CR2 groups. CONCLUSION: B-ultrasound measurement can quantitatively reflect muscle strength following gracilis transfer, and CR value could be a potential indicator for functional recovery of the transplanted gracilis muscle. LEVEL OF EVIDENCE: Prognostic studies, Level II.

Trehalose protects motorneuron after brachial plexus root avulsion by activating autophagy and inhibiting apoptosis mediated by the AMPK signaling pathway.

Brachial plexus root avulsion (BPRA) is one of the most serious injuries of the upper extremity, which requires more effective treatment. Trehalose, a natural disaccharide, has reported to has a protective effect in neurodegenerative diseases. However, the effective effects and mechanism of trehalose on BPRA are still unclear. BPRA rat model were established, and then effects of trehalose on BPRA were investigated. TBHP-treated NSC34 cells with or without trehalose treatment were used for mechanism studies by Western blotting, Immunofluorescence and Flow cytometry analysis. Trehalose elevated the survival of motor neurons in rats after BPRA, suggesting a protective role of trehlose on BPRA. Trehalose treatment in rats after BPRA enhanced the autophage and thus inhibited apoptosis compared with rats in Vehicle group. Moreover, in TBHP-treated NSC34 cells, trehalose promoted the expression of autophage-related markers (LC3 and Beclin-1), concomitant with decreased levels of apoptosis. In vitro mechanism study indicated that the regulations of trehalose on autophage and apoptosis were via the AMPK-ULK1 pathway. Trehalose protects injured MNs by enhancing autophage and inhibiting apoptosis, which demonstrating the essential role of trehalose in the prevention and treatment of BPRA.

Electrochemical detection of methyl-paraoxon based on bifunctional cerium oxide nanozyme with catalytic activity and signal amplification effect / 药物分析学报

A new electrochemical sensor for organophosphate pesticide(methyl-paraoxon)detection based on bifunctional cerium oxide(CeO2)nanozyme is here reported for the first time.Methyl-paraoxon was degraded into p-nitrophenol by using CeO2 with phosphatase mimicking activity.The CeO2 nanozyme-modified electrode was then synthesized to detect p-nitrophenol.Cyclic voltammetry was applied to investigate the electrochemical behavior of the modified electrode,which indicates that the signal enhancement effect may attribute to the coating of CeO2 nanozyme.The current research also studied and discussed the main parameters affecting the analytical signal,including accumulation potential,accumulation time,and pH.Under the optimum conditions,the present method provided a wider linear range from 0.1 to 100 μmol/L for methyl-paraoxon with a detection limit of 0.06 μmol/L.To validate the proof of concept,the electrochemical sensor was then successfully applied for the determination of methyl-paraoxon in three herb samples,i.e.,Coix lacryma-jobi,Adenophora stricta and Semen nelum-binis.Our findings may provide new insights into the application of bifunctional nanozyme in electro-chemical detection of organophosphorus pesticide.

Local Riluzole Release from a Thermosensitive Hydrogel Rescues Injured Motoneurons through Nerve Root Stumps in a Brachial Plexus Injury Rat Model.

The C5-C6 nerve roots are usually spared from avulsion after brachial plexus injury (BPI) and can thus be used as donors for nerve repair. A BPI rat model with C5-C6 nerve root stumps has been established in our previous work. The aim of this study was to test whether riluzole loaded into a thermosensitive hydrogel could applied locally in the nerve root stumps of this BPI rat model, thus increasing the reparative effect of the nerve root stumps. Nile red (a hydrophobic dye) was used as a substitute for riluzole since riluzole itself does not emit light. Nile red, loaded into a thermosensitive hydrogel, was added to the nerve root stumps of the BPI rat model. Additionally, eighteen rats, with operation on right brachial plexus, were evenly divided into three groups: control (Con), thermosensitive hydrogel (Gel) and thermosensitive hydrogel loaded with riluzole (Gel + Ri) groups. Direct nerve repair was performed after local riluzole release for two weeks. Functional and electrophysiological evaluations and histological assessments were used to evaluate the reparative effect 8 weeks after nerve repair. Nile red was slowly released from the thermosensitive hydrogel and retrograde transport through the nerve root stumps to the motoneurons, according to immunofluorescence. Discernible functional recovery began earlier in the Gel + Ri group. The compound muscle action potential, ChAT-expressing motoneurons, positivity for neurofilaments and S100, diameter of regenerating axons, myelin sheath thickness and density of myelinated fibers were markedly increased in the Gel + Ri group compared with the Con and Gel groups. Our results indicate that the local administration of riluzole could undergo retrograde transportation through C5-C6 nerve root stumps, thereby promoting neuroprotection and increasing nerve regeneration.

miR­217­5p regulates myogenesis in skeletal muscle stem cells by targeting FGFR2.

MicroRNA-217-5p (miR-217-5p) has been implicated in cell proliferation; however, its role in skeletal muscle stem cells (SkMSCs) remains unknown. The present study aimed to explore the roles of miR­217­5p in the biological characteristics of SkMSCs. SkMSCs were identified by cell surface markers using flow cytometry. The present study observed that miR­217­5p mimics accelerated the proliferation and suppressed the differentiation in SkMSCs. In addition, the results of the present study revealed that fibroblast growth factor receptor 2 (FGFR2) was a target of miR­217­5p, as miR­217­5p bound directly to the 3'­untranslated region of FGFR2 mRNA, resulting in increased FGFR2 mRNA and protein levels. In addition, the present study suppressed the expression of FGFR2 in SkMSCs using a selective FGFR inhibitor AZD4547 and detected the efficiency of inhibition by reverse transcription­quantitative PCR and western blotting. miR­217­5p levels were positively associated with FGFR2 expression, which was upregulated and accelerated the proliferation of SkMSCs compared with that of the miR­NC group. Collectively, these results demonstrated that miR­217­5p may act as a myogenesis promoter in SkMSCs by directly targeting FGFR2 and may regulate the myogenesis of these cells.

Exploration of Potential Roles of m6A Regulators in Colorectal Cancer Prognosis.

Colorectal cancer (CRC) represents one of the most common malignancies with high morbidity worldwide. RNA methylation (m6A) has been considered to tremendously contribute to cancer initiation and progression since its first discovery. In this study, we comprehensively analyzed associations between mRNA expressions of m6A regulators and CRC tumor samples' epidemiologic information from the Cancer Genome Atlas (TCGA). Multivariate Cox proportional hazard model was applied to screening of m6A regulators whose mRNA expressions were significantly associated with CRC tumor samples' overall survival (OS) probability and those significant regulators were used for LASSO regression analysis to construct CRC prognosis prediction signature. As a result, two regulators i.e., YTHDC2 and ALKBH5 were picked out in multivariate analysis. CRC prognosis signature was constructed based on those two regulators through which CRC tumor samples with favorable and inferior prognosis could definitely be distinguished independent of potential confounding factors. This study should be helpful for identifying prognostic different CRC patients and guiding therapeutic method selection.