Objective: Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS.An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS.In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice.Methods: A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords.Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days.The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment.The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs).The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. Results:The area of demyelination in the spinal cord was significantly reduced in the COG112 group.EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter.Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls.TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. Conclusion:The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model of CNS demyelination.These data support that apoE-mimetic strategy may represent a promising therapy for MS and other demyelination disorders.
Many studies demonstrate that the type of adjacent mesenchymal cells can affect epidermal morphogenesis of bilayered tissue-engineered skin. However, whether a mixture of different mesenchymal cell types can improve epidermal morphogenesis of bioengineered skin remains unknown. In this study, keratinocytes, dermal fibroblasts and adipose tissue-derived stem cells (ADSCs) were isolated and purified from human skin and subcutaneous fat. Conditioned medium generated from a mixture of dermal fibroblasts and ADSCs at the ratio of 1:1 was superior to that from fibroblasts or ADSCs alone in promoting keratinocyte proliferation, as indicated by MTT assay. Furthermore, ELISA results showed that the cytokine levels of human hepatocyte growth factor and keratinocyte growth factor (also known as FGF7) in the mixed fibroblasts/ADSC group were higher than those in the ADSC or dermal fibroblasts group. To examine the potential roles of mixed fibroblasts and ADSCs on epidermal morphogenesis, a three-dimensional tissue engineered skin system was applied. Histological analyses demonstrated that keratinocytes proliferated extensively over the mixture of fibroblasts and ADSCs, and formed a thick epidermal layer with well-differentiated structures. Keratin 10 (epidermal differentiation marker) was expressed in the suprabasal layer of bilayered tissue-engineered skin in the mixed fibroblasts and ADSCs group. Desmosomes and hemidesmosomes were detected in the newly formed epidermis by transmission electron microscopy analysis. Together, these findings revealed for the first time that a mixture of fibroblasts and ADSCs in bilayered tissue-engineered skin can improve epidermal morphogenesis.
Spasticity commonly emerges during the process of recovery after spinal cord injury (SCI) and critically exacerbates motor dysfunction. Given the insufficient effect of individual therapy on solving these problems, in this study, we conducted repetitive transcranial magnetic stimulation (rTMS) with treadmill training (Tr) in rats with SCI to investigate the potential synergistic effects on alleviating spasticity and motor dysfunction. After eight-week intervention, the Tr plus rTMS-Tr group showed a significant decrease in Hmax/Mmax amplitude ratio and an improvement in motor function, as revealed by Basso, Beattie, and Bresnahan (BBB) locomotor scale and the grid-walking test. These effects of combined treatment of rTMS and treadmill training were enhanced remarkably than treadmill training alone. Furthermore, pathological analyses demonstrated that the combined treatment facilitated the growth of serotonergic axons around the lesion site, and the upregulation of 5-hydroxytryptamine (5-HT), potassium-chloride cotransporter-2 (KCC2), and glutamic acid decarboxylases 67 (GAD67) in the lumbar spinal cord distal to the injury site. These results suggest that treadmill training and rTMS intervention have synergistic effects on spasticity and locomotion, which is related to a restored balance between facilitatory and inhibitory inputs to motoneurons.
Abstract As the central hub of the metabolism machinary, mTORC2 has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. It has been reported that Rictor is involved in B cell development, especially the peripheral development. But the role of Rictor on BCR signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell specfic Rictor knockout mice (cd19Cre) to investigate how Rictor regulates BCR signaling. We found that for the key positive and negative BCR signaling molecules, pBtk is reduced and pSHIP is enhanced in Rictor KO B cells. This indicates Rictor positively regulates the early events of B cell receptor (BCR) signaling. We found that the cellular F-actin is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing the BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration leads to decreases in the humoral immune response in Rictor KO mice. The inhibition of actin polymerization with Latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, where Rictor regulates BCR signaling via actin reorganization.
Abstract Aims This study aims to investigate the epidemiological characteristics of COVID‐19 infection among healthcare workers, including the severity, duration of infection, post‐infection symptoms and related influencing factors. Methods A self‐administered questionnaire was utilized to assess the post‐infection status of primary healthcare workers in Jiangsu Province. The questionnaire collected information on demographic characteristics, lifestyle habits, post‐infection clinical manifestations, work environment and recovery time of the respondents. Customized outcome events were selected as dependent variables and logistic regression models were employed to analyse the risk factors. Phi‐coefficient was used to describe the relationship between post‐infection symptoms. Results The analysis revealed that several factors, such as female, older age, obesity, previous medical history, exposure to high‐risk environments and stress, were associated with a higher likelihood of experiencing more severe outcomes. On the other hand, vaccination and regular exercise were found to contribute to an earlier resolution of the infection. Among the post‐infection symptoms, cough, malaise and muscle aches were the most frequently reported. Overall, there was a weak association among symptoms persisting beyond 14 days, with only cough and malaise, malaise and dizziness and headache showing a stronger correlation. Conclusion The study findings indicate that the overall severity of the first wave of infection, following the complete lifting of restrictions in China, was low. The impact on primary healthcare workers was limited, and the post‐infection symptoms exhibited similarity to those observed in other countries. It is important to highlight that these conclusions are specifically relevant to the population infected with the Omicron variant. Impacts This study helps to grasp the impacts of the first wave of COVID‐19 infections on healthcare workers in China after the national lockdown was lifted. Patients Primary healthcare workers in Jiangsu Province, including doctors, nurses, pharmacists and other personnel from primary healthcare units such as community health service centres and health centres.
Background: To explore the new biomarkers for coronary artery disease detection and improved therapeutic targets, the comprehensive understanding of protein networks and protein expression abundance in coronary artery samples were established by means of LC-MS/MS analysis.Methods: 20 human coronary artery specimens from 2 autopsied adults were employed in the study. The natural history and histological classification of atherosclerotic lesions of the coronary artery samples were analyzed by Haematoxylin and Eosin (H&E) staining, and the human coronary arterial proteome and proteomic features was characterized by mass spectrometry analysis.Findings: In the present study, we identified 2135 proteins in the 20 coronary artery segments samples from 2 cases. Combination with the results of Haematoxylin and Eosin (H&E) staining of coronary artery samples, a total of 174 proteins, including 4 upregulated proteins and 164 downregulated proteins were obtained which associated with coronary artery disease. And, GO and KEGG enrichment of the differentially expressed proteins shown that the mitochondrial energy metabolism maybe underlying in the occurrence and development of coronary artery atherosclerosis.Interpretation: The human coronary arterial proteome can be considered as a complex network whose architectural characteristics vary considerably as a function of the presence or absence, and histological classification of coronary artery atherosclerosis. The data suggest that the prevention of mitochondrial dysfunction via retrieve the mitochondrial associated proteins expression may be a promising target in coronary artery disease.Funding Statement: This study received support from the National Natural Science Foundations of China (grants 81170180, 30400173, 30971257 and 81970302) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. Dr. Enzhi Jia is an Assistant Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.Declaration of Interests: The authors declare no potential conflicts of interest.Ethics Approval Statement: Informed consent from the bereaved family was obtained for the research use only of samples and the autopsy was conducted according to the guideline of the university. The methods were performed in accordance with the approved guidelines, and all experimental protocols were approved by the ethics committee of the Nanjing Medical University and the First Affiliated Hospital of Nanjing Medical University.
Gonadotropin-releasing hormone (GnRH) is a key factor at the onset of puberty. This decapeptide has been found in mammalian ovaries, but its regulatory mechanism in the ovary of sheep at the onset of puberty is not clear. This study investigated the coding sequence (CDS) of the GnRH gene in the ovary of Duolang sheep and the expression of GnRH mRNA in different tissues at the onset of puberty, and analyzed the effect of GnRH on ovarian granulosa cells (GCs) of Duolang sheep. The results showed that the GnRH CDS of sheep was cloned, the full length of the GnRH CDS in sheep ovary was 279 bp, and the nucleotide sequence was completely homologous to that in the hypothalamus. The expression of GnRH mRNA was highest in the hypothalamus and ovary. The expression of related hormones and receptors in GCs of Duolang sheep treated with different concentrations of GnRH for 24 h was affected. GnRH significantly inhibited LH synthesis and LHR expression in GCs. Low concentration (100 ng mL -1 ) had the most obvious therapeutic effect on follicle-stimulating hormone (FSH) and FSHR. Higher concentration (250 ng mL -1 ) significantly promoted estradiol and ERβ mRNA. These findings provide strong evidence that ovarian GnRH is an important regulatory factor at the onset of puberty in sheep.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)