A shear-thinning, ROS-scavenging hydrogel combined with dental pulp stem cells promotes spinal cord repair by inhibiting ferroptosis.

Spinal cord injury (SCI) is a serious clinical disease. Due to the deformability and fragility of the spinal cord, overly rigid hydrogels cannot be used to treat SCI. Hence, we used TPA and Laponite to develop a hydrogel with shear-thinning ability. This hydrogel exhibits good deformation, allowing it to match the physical properties of the spinal cord; additionally, this hydrogel scavenges ROS well, allowing it to inhibit the lipid peroxidation caused by ferroptosis. According to the in vivo studies, the TPA@Laponite hydrogel could synergistically inhibit ferroptosis by improving vascular function and regulating iron metabolism. In addition, dental pulp stem cells (DPSCs) were introduced into the TPA@Laponite hydrogel to regulate the ratios of excitatory and inhibitory synapses. It was shown that this combination biomaterial effectively reduced muscle spasms and promoted recovery from SCI.

Genome-wide identification and characterization of OVATE family proteins in Betula luminifera reveals involvement of BlOFP3 and BlOFP5 genes in leaf development.

Ovate family proteins (OFP) are plant-specific transcription factors involved in regulating morphologies of the lateral organs, plant growth and development. However, the functional roles of OFP genes in Betula luminifera, an important timber tree species, are not well studied. In this study, we identified 20 BlOFP genes and analyzed their phylogenetic relationship, gene structure, conserved motifs, and cis-elements. Further, expression analysis indicates that BlOFP genes were up-regulated in leaves on the one-year-old branch compared to leaves on the current-year branch and bract, except BlOFP7, BlOFP11, BlOFP14 and BlOFP12. The overexpression of BlOFP3 and BlOFP5 in Arabidopsis thaliana not only resulted in a slower growth rate but also produced sawtooth shape, flatter and darker green rosette leaves. Further investigation showed that the leaf thickness of the transgenic plants was more than double that of the wild type, which was caused by the increasement in the number and size of palisade tissue cells. Furthermore, the expression analysis also indicated that the expressions of several genes related to leaf development were significantly changed in the transgene plants. These results suggested the significant roles of BlOFP3 and BlOFP5 in leaf development. Moreover, protein-protein interaction studies showed that BlOFP3 interacts with BlKNAT5, and BlOFP5 interacts with BlKNAT5, BlBLH6 and BlBLH7. In conclusion, our study demonstrates that BlOFP3 and BlOFP5 were involved in leaf shape and thickness regulation by forming a complex with BlKNAT5, BlBLH6 and BlBLH7. In addition, our study serves as a guide for future functional genomic studies of OFP genes of the B. luminifera.

Corrigendum: Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis.

[This corrects the article DOI: 10.3389/fcell.2021.693694.].

Nerve growth factor (NGF) with hypoxia response elements loaded by adeno-associated virus (AAV) combined with neural stem cells improve the spinal cord injury recovery.

The ischemia and hypoxia microenvironment after spinal cord injury (SCI) makes SCI repair a challenging problem. With various stimulus, chances for neural stem cells (NSCs) to differentiate into neurons, astrocytes, oligodendrocytes are great and is considered as a potential source of the stem cell therapy to SCI. Our research used adeno-associated virus (AAV) to carry the target gene to transfect neural stem cells. Transfected NSCs can express nerve growth factor (NGF) navigated by five hypoxia-responsive elements (5HRE). Therefore, the 5HRE-NGF-NSCs could express NGF specifically in hypoxia sites to promote the tissue repair and function recovery. Based on the regeneration of neurocytes and promotion of the recovery found in SCI models, via locomotor assessment, histochemical staining and molecular examinations, our results demonstrated that 5HRE-NGF-NSCs could improve the motor function, neurons survival and molecules expression of SCI rats. Meanwhile, the downregulated expression of autophagy-related proteins indicated the inhibitive effect of 5HRE-NGF-NSCs on autophagy. Our research showed that 5HRE-NGF-NSCs contribute to SCI repair which might via inhibiting autophagy and improving the survival rate of neuronal cells. The new therapy also hampered the hyperplasia of neural glial scars and induced axon regeneration. These positive functions of 5HRE-NGF-NSCs all indicate a promising SCI treatment.

Hypoxia Response Element-Directed Expression of aFGF in Neural Stem Cells Promotes the Recovery of Spinal Cord Injury and Attenuates SCI-Induced Apoptosis.

Reducing neuronal death after spinal cord injury (SCI) is considered to be an important strategy for the renovation of SCI. Studies have shown that, as an important regulator of the development and maintenance of neural structure, acidic fibroblast growth factor (aFGF) has the role of tissue protection and is considered to be an effective drug for the treatment of SCI. Neural stem cells (NSCs) are rendered with the remarkable characteristics to self-replace and differentiate into a variety of cells, so it is promising to be used in cell transplantation therapy. Based on the facts above, our main aim of this research is to explore the role of NSCs expressing aFGF meditated by five hypoxia-responsive elements (5HRE) in the treatment of SCI by constructing AAV-5HRE-aFGF-NSCs and transplanting it into the area of SCI. Our research results showed that AAV-5HRE-aFGF-NSCs can effectively restore the motor function of rats with SCI. This was accomplished by inhibiting the expression of caspase 12/caspase 3 pathway, EIF2α-CHOP pathway, and GRP78 protein to inhibit apoptosis.

Metabolomics reveals sex-specific metabolic shifts and predicts the duration from positive to negative in non-severe COVID-19 patients during recovery process.

Metabolic profiling in COVID-19 patients has been associated with disease severity, but there is no report on sex-specific metabolic changes in discharged survivors. Herein we used an integrated approach of LC-MS-and GC-MS-based untargeted metabolomics to analyze plasma metabolic characteristics in men and women with non-severe COVID-19 at both acute period and 30 days after discharge. The results demonstrate that metabolic alterations in plasma of COVID-19 patients during the recovery and rehabilitation process were presented in a sex specific manner. Overall, the levels of most metabolites were increased in COVID-19 patients after the cure relative to acute period. The major plasma metabolic changes were identified including fatty acids in men and glycerophosphocholines and carbohydrates in women. In addition, we found that women had shorter length of hospitalization than men and metabolic characteristics may contribute to predict the duration from positive to negative in non-severe COVID-19 patients. Collectively, this study shed light on sex-specific metabolic shifts in non-severe COVID-19 patients during the recovery process, suggesting a sex bias in prognostic and therapeutic evaluations based on metabolic profiling.

Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats.

Cell-based transplantation strategies possess great potential for spinal cord injury (SCI) repair. Basic fibroblast growth factor (bFGF) has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following SCI. Human dental pulp stem cells (DPSCs) are abundant stem cells with low immune rejection, which can be considered for cell replacement therapy. The purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements (5HRE) using an adeno-associated virus (AAV-5HRE-bFGF-DPSCs) in SCI repairing model. In this study, DPSCs were revealed to differentiate into CD13+ pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13+ pericytes to vascular endothelial cells. The re-attachment of CD13+ pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of protuberance. As a result, increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was improved. Thus, this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.

Correlation Study of Short-Term Mental Health in Patients Discharged After Coronavirus Disease 2019 (COVID-19) Infection without Comorbidities: A Prospective Study.

OBJECTIVE: The WHO has upgraded the status of coronavirus disease 2019 (COVID-19) from epidemic to global pandemic. The psychometric properties aspects of COVID-19 patients without comorbidities in the short term after discharge have not been reported. In this study, the Short Form 36 (SF-36) was used to evaluate the psychometric properties and to find relevant risk factors. METHODS: The study was conducted in seven hospitals from January 2020 to April 2020. The SF-36 questionnaire was administered one month after discharge. Univariate analysis and multivariate regression model were used to analyze the risk factors of psychometric properties impairment. RESULTS: In univariate analysis of independent risk factors, according to the comparison of whether the duration of positive nucleic acid was greater than 20 days, the positive nucleic acid duration was independently related to the decreased role-emotional value [100, IQR (66-100) vs 100, IQR (0, 100); p = 0.0156]. In addition, multivariable linear regression model showed that male sex and positive nucleic acid duration were related to decreased role-emotional value (p = 0.03< 0.05; p = 0.01< 0.05, respectively). Mental health was associated with age (p= 0.0435). Subsequently, we divided into three subgroups: less than seven days, 7 to 14 days and more than 14 days according to the positive nucleic acid duration. The results revealed that there were significant differences in the vitality value and mental health value of patients aged 46 to 69 in the subgroup where the positive nucleic acid duration longer than 14 days (p= 0.0472; p= 0.0311< 0.05, respectively). Similarly, there are also significant differences in role-emotional value in different genders (p= 0.0316). CONCLUSION: The study described the psychometric properties of COVID-19 patients without comorbidities shortly after discharge. Risk factors for psychometric properties damage included age, male sex, and nucleic acid duration.

Systemic Administration of Fibroblast Growth Factor 21 Improves the Recovery of Spinal Cord Injury (SCI) in Rats and Attenuates SCI-Induced Autophagy.

Protecting the death of nerve cells is an essential tactic for spinal cord injury (SCI) repair. Recent studies show that nerve growth factors can reduce the death of nerve cells and promote the healing of nerve injury. To investigate the conducive effect of fibroblast growth factor 21 (FGF21) on SCI repair. FGF21 proteins were systemically delivered into rat model of SCI via tail vein injection. We found that administration of FGF21 significantly promoted the functional recovery of SCI as assessed by BBB scale and inclined plane test, and attenuated cell death in the injured area by histopathological examination with Nissl staining. This was accompanied with increased expression of NeuN, GAP43 and NF200, and deceased expression of GFAP. Interestingly, FGF21 was found to attenuate the elevated expression level of the autophagy marker LC3-II (microtubules associated protein 1 light chain 3-II) induced by SCI in a dose-dependent manner. These data show that FGF21 promotes the functional recovery of SCI via restraining injury-induced cell autophagy, suggesting that systemic administration of FGF21 could have a therapeutic potential for SCI repair.

microRNA­372 inhibits proliferation and induces apoptosis in human breast cancer cells by directly targeting E2F1.

Breast cancer is the most prevalent cancer and the leading cause of cancer­associated mortalities among women worldwide today. Accumulating evidence suggested that miR­372 may serve important roles in the initiation and development of various human cancers. However, the role of miR­372 in breast cancer remains unknown. The present study demonstrated that the expression level of miR­372 in human breast cancer tissues and cell lines is significantly reduced compared with normal breast tissues cell lines. Furthermore, results of functional assays indicated that miR­372 inhibits cell proliferation and induces apoptosis in the MCF­7 human breast cancer cell line. E2F1 was identified as a direct functional target of miR­372 in breast cancer. In conclusion, the findings revealed that miR­372 may have the potential to act as a novel molecule for the diagnosis and therapy of patients with breast cancer.

Posttreatment with Protectin DX ameliorates bleomycin-induced pulmonary fibrosis and lung dysfunction in mice.

Protectin DX (10S,17S-dihydroxydocosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid) (PDX), generated from Ω-3 fatty docosahexaenoic acids, is believed to exert anti-inflammatory and proresolution bioactions. To date, few studies have been performed regarding its effect on pulmonary fibrosis. Herein we show that PDX exerts a potential therapeutic effect which is distinct from its anti-inflammation and pro-resolution activity on mice with pulmonary fibrosis. In the present study, we showed that bleomycin (BLM) increased inflammatory infiltration, collagen deposition, and lung dysfunction on day7 after challenged in mice. Posttreatment with PDX ameliorated BLM-induced inflammatory responses, extracellular matrix (ECM) deposition and the level of cytokines related to fibrosis as evaluated by histology analysis, transformation electron microscope (TEM), lung hydroxyproline content and cytokines test. Moreover, PDX improved lung respiratory function, remedied BLM-induced hypoxemia and prolonged life span. In addition, we found that PDX reversed epithelial-mesenchymal transition (EMT) phenotypic transformation in vivo and in vitro, reinforcing a potential mechanism of promoting fibrosis resolution. In summary, our findings showed that posttreatment with PDX could ameliorate BLM-induced pulmonary fibrosis and lung dysfunction in mice and PDX may be considered as a promising therapeutic approached to fibrotic lung diseases.

Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway.

Maresin1 (MaR1) is a new docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. In this study, we sought to investigate the effect and underlining mechanisms of MaR1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. MaR1 was injected intravenously or administered by instillation (200 ng/kg) 8 h after LPS (14 mg/kg) administration and AFC was measured in live rats. In primary rat alveolar type II epithelial cells, MaR1 (100 nM) was added to the culture medium with lipopolysaccharide for 6 h. MaR1 markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema and lung injury. In addition, rat lung tissue protein was isolated after intervention, and we found MaR1 improved epithelial sodium channel (ENaC), Na,K-adenosine triphosphatase (ATPase) protein expression and Na,K-ATPase activity. MaR1 down-regulated Nedd4-2 protein expression though PI3k/Akt but not though PI3k/SGK1 pathway in vivo. In primary rat alveolar type II epithelial cells stimulated with LPS, MaR1-upregulated ENaC and Na,K-ATPase protein abundance in the plasma membrane. Finally, the lipoxin A4 Receptor inhibitor (BOC-2) and PI3K inhibitor (LY294002) not only blocked MaR1's effects on cAMP/cGMP, the expression of phosphorylated Akt and Nedd4-2, but also inhibited the effect of MaR1 on AFC in vivo. In conclusion, MaR1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway. Our findings reveal a novel mechanism for pulmonary edema fluid reabsorption and MaR1 may provide a new therapy for the resolution of ALI/ARDS.

Determination of dexmedetomidine in children's plasma by ultra-performance liquid chromatography tandem mass spectrometry and application to pharmacokinetic study.

A rapid, sensitive, and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of dexmedetomidine in children's plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2mL of acetonitrile to a 0.1mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.1min and the elution of dexmedetomidine was at 1.24min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring mode using the respective transitions m/z 201.3→95.1 for dexmedetomidine and m/z 204.2→98.0 for the internal standard, respectively. The calibration curve was linear over the range of 0.05-10ng/mL with a lower limit of quantitation of 0.05ng/mL. Mean recovery rate of dexmedetomidine in plasma was in the range of 86.7-89.1%. Intra-day and inter-day precision were both <11.6%. This method was successfully applied in pharmacokinetic study after commencement of 1.0µg/kg dexmedetomidine infusion in children.