Exosomal microRNA-Based therapies for skin diseases.

Based on engineered cell/exosome technology and various skin-related animal models, exosomal microRNA (miRNA)-based therapies derived from natural exosomes have shown good therapeutic effects on nine skin diseases, including full-thickness skin defects, diabetic ulcers, skin burns, hypertrophic scars, psoriasis, systemic sclerosis, atopic dermatitis, skin aging, and hair loss. Comparative experimental research showed that the therapeutic effect of miRNA-overexpressing exosomes was better than that of their natural exosomes. Using a dual-luciferase reporter assay, the targets of all therapeutic miRNAs in skin cells have been screened and confirmed. For these nine types of skin diseases, a total of 11 animal models and 21 exosomal miRNA-based therapies have been developed. This review provides a detailed description of the animal models, miRNA therapies, disease evaluation indicators, and treatment results of exosomal miRNA therapies, with the aim of providing a reference and guidance for future clinical trials. There is currently no literature on the merits or drawbacks of miRNA therapies compared with standard treatments.

Exosomal-microRNAs Improve Islet Cell Survival and Function In Islet Transplantation.

Exosomal-microRNAs (Exo-miRNAs) are key regulators of islet cell function, including insulin expression, processing, and secretion. Exo-miRNAs have a significant impact on the outcomes of islet transplantation as biomarkers for evaluating islet cell function and survival. Furthermore, they have been linked to vascular remodeling and immune regulation following islet transplantation. Mesenchymal stem cell-derived exosomes have been shown in preliminary studies to improve islet cell viability and function when injected or transplanted into mice. Overall, Exo-miRNAs have emerged as novel agents for improving islet transplantation success rates. The role of islet-derived Exo-miRNAs and mesenchymal stem cells-derived Exo-miRNAs as biomarkers and immunomodulators in islet regeneration, as well as their role in improving islet cell viability and function in islet transplantation, are discussed in this review.

Transplantation of insulin-producing cells derived from human MSCs to treat diabetes in a non-human primate model.

BACKGROUND: Islet cell transplantation is an emerging therapy in the treatment of diabetes mellitus. Differentiation of islet cells from mesenchymal stem cells (MSCs) is a potential solution to the challenge of insufficient donor sources. This study investigated whether human umbilical cord-derived MSCs could effectively differentiate into insulin-producing cells (IPCs) and evaluated the therapeutic efficacy of IPCs in treating diabetes. METHODS: IPCs were induced from MSCs by a two-step protocol. IPC expression products were evaluated by western blot and real-time PCR. IPC insulin secretion was evaluated by ELISA. The viability of IPCs was measured by FDA/PI and dithizone staining. The non-human primate tree shrew was used as a diabetes model. After a single STZ induction into a diabetes model, a single intraportal transplantation of IPCs, MSCs, or normal saline was performed (n = 6 per group). Blood glucose was monitored for 3 weeks, then the animals were euthanized and the distribution of IPCs in the liver was examined pathologically. RESULTS: After about 3 weeks of in vitro induction, IPCs formed microspheres of 100-200 µm, with >95% viable cells that were dithizone stain positive. IPCs expressed islet-related genes and proteins and secreted high levels of insulin whether stimulated by low or high levels of glucose. After transplantation of IPCs into diabetic tree shrews, blood glucose levels decreased rapidly to near normal and were significantly lower than the MSC or saline groups for 3 weeks thereafter. CONCLUSION: We present the novel discovery that IPCs derived from human umbilical cord MSCs exert a therapeutic effect in a non-human primate model of diabetes. This study provides a preliminary experimental basis for the use of autologous MSC-derived IPCs in the treatment of human diabetes.

Exosomal microRNAs as diagnostic biomarkers and therapeutic applications in neurodegenerative diseases.

Originating from slow irreversible and progressive loss and dysfunction of neurons and synapses in the nervous system, neurodegenerative diseases (NDDs) affect millions of people worldwide. Common NDDs include Parkinson's disease, Alzheimer's disease multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Currently, no sensitive biomarkers are available to monitor the progression and treatment response of NDDs or to predict their prognosis. Exosomes (EXOs) are small bilipid layer-enclosed extracellular vesicles containing numerous biomolecules, including proteins, nucleic acids, and lipids. Recent evidence indicates that EXOs are pathogenic participants in the spread of neurodegenerative diseases, contributing to disease progression and spread. EXOs are also important tools for diagnosis and treatment. Recently, studies have proposed exosomal microRNAs (miRNAs) as the targets for therapies or biomarkers of NDDs. In this review, we outline the latest research on the roles of exosomal miRNAs in NDDs and their applications as potential diagnostic and therapeutic biomarkers, targets, and drugs for NDDs.

Analysis of key genes and targeted protection methods affecting the survival of human islets / 器官移植

Objective To identify the key genes and targeted protection methods affecting the survival of human islets. Methods Using bioinformatics method, the gene expression profile (GSE53454) was selected through screening and comparison from Gene Expression Omnibus(GEO) database. GEO2R tool was employed to screen the differentially expressed gene(DEG) between the human islets exposed (exposure group) and non-exposed (non-exposure group) to interleukin (IL)-1β and interferon (IFN)-γ for 24, 48 and 72 h, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by DAVID. Protein-protein interaction (PPI) network was constructed by STRING and Cytoscape apps. Results A total of 69 up-regulated DEGs and 2 down-regulated DEGs were identified. GO analysis showed that during the biological process, DEGs were enriched in the aspects of virus defense and inflammatory response. In cellular components, DEGs were significantly enriched in extracellular space, outside plasma membrane and extracellular regions. Regarding molecular functions, DEGs were significantly enriched in chemokine activity and cytokine activity. KEGG analysis revealed that DEGs were mainly enriched in multiple signaling pathways, such as cytokine-cytokine receptor interaction, virus protein-cytokine and cytokine-receptor interaction, etc. Ten key genes (STAT1, CXCL10, IRF1, IL6, CXCL9, CCL5, CXCL11, ISG15, CD274, IFIT3) with high connectivity were selected by STRING analysis, all of which were significantly up-regulated in human islets exposed to IL-1β and IFN-γ. Six genes (STAT1, CXCL10, CXCL9, CXCL11, CCL5, IL6) were screened by KEGG enrichment analysis, mainly in Toll-like receptor signaling pathway. Conclusions STAT1, CXCL10, CXCL9, CXCL11, CCL5 and IL6 are the key genes affecting the survival of human islets, which are mainly enriched in Toll-like receptor signaling pathway and act as important targets for islet protection.

In vitro research of mesenchymal stem cell-coated human islets to alleviate instant blood-mediated inflammatory reaction / 器官移植

Objective To evaluate the effect of mesenchymal stem cell (MSC) coated-islets on instant blood-mediated inflammatory reaction (IBMIR) after islet transplantation. Methods MSC labeled with tracer and human islets were placed into an ultra-low adsorption cell culture dish, shaken and mixed twice at an interval of 0.5 h, and then incubated at 37 ℃ and 5% CO2 for 24 h to obtain MSC-coated islets. The coating effect of MSC and in vitro function of the islets were assessed. A blood circulation tube-shaped model was established in vitro. In the blank control group, 0.2 mL of islet culture solution was added. In the islet group, 800 islet equivalent quantity (IEQ) of uncoated islets were supplemented. In the MSC-coated islets group, 800 IEQ of MSC-coated islets were added, and circulated for 60 min at 37 ℃. A portion of 0.5 mL blood sample was taken for routine blood test at 0, 30 and 60 min, respectively. After 60 min circulation, the blood sample was filtered with a 70 μm filter to collect plasma, blood clots and islets. Blood clots and islets were subject to hematoxylin-eosin (HE) staining and immunohistochemical staining. Morphological changes and the aggregation of CD11b-positive cells surrounding the islets were observed. The contents of plasma thrombin-antithrombin complex (TAT), tissue factor (TF), C3a, C5b-9, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1 and IL-8 were determined by enzyme-linked immune absorbent assay. Results After 24 h co-incubation, the islets were coated by MSC, with a coating degree of approximately 80%. In the islet and MSC-coated islet group, a large quantity of neutrophils and monocytes were observed surrounding the blood clots and islets, and the quantity of CD11b-positive cells in the MSC-coated islet group was less compared with that in the islet group. After co-incubation with the whole blood for 0, 30 and 60 min, the quantity of platelets, neutrophils and monocytes was declined in the MSC-coated and islet groups, and gradually decreased over time. Compared with the blank control group, the quantity of platelets, monocytes and neutrophils was lower, whereas the TF content was higher in the MSC-coated islet group. Compared with the islet group, the quantity of platelets, monocytes and neutrophils was higher, whereas the TAT and TF contents were less in the MSC-coated islet group, the differences were statistically significant (all P < 0.05). Compared with the blank control group, the expression levels of C3a, C5b-9, IL-6, TNF-α and IL-8 were up-regulated in the MSC-coated islet group. Compared with the islet group, the expression levels of C3a, C5b-9, IL-1β, IL-6, TNF-α, IL-8 and MCP-1 were down-regulated in the MSC-coated islet group, and the differences were statistically significant (all P < 0.05). Conclusions MSC-coated islets may reduce the exposure of islet TF in the blood and prevent the incidence of IBMIR during the coagulation response stage, thereby mitigating the injury and loss of islet allograft in the early stage of islet transplantation.

Therapeutic strategy for instant blood-mediated inflammatory reaction after islet transplantation / 器官移植

As an effective procedure for type 1 diabetes mellitus and end-stage type 2 diabetes mellitus, islet transplantation could enable those patients to obtain proper control of blood glucose levels. Instant blood-mediated inflammatory reaction (IBMIR) is a nonspecific inflammation during early stage after islet transplantation. After IBMIR occurs, coagulation cascade, complement system activation and inflammatory cell aggregation may be immediately provoked, leading to loss of a large quantity of transplant islets, which severely affects clinical efficacy of islet transplantation. How to alleviate the islet damage caused by IBMIR is a hot topic in islet transplantation. Heparin and etanercept, an inhibitor of tumor necrosis factor-α, are recommended as drugs for treating IBMIR following islet transplantation. Recent studies have demonstrated that multiple approaches and drugs may be adopted to mitigate the damage caused by IBMIR to the islets. In this article, the findings in clinical and preclinical researches were reviewed, aiming to provide reference for the management of IBMIR after islet transplantation.

Research on performance optimization method of human-machine physical interaction system considering exoskeleton wearing comfort / 生物医学工程学杂志

In order to improve the wearing comfort and bearing effectiveness of the exoskeleton, based on the prototype and working mechanism analysis of a relaxation wearable system for knee exoskeleton robot, the static optimization synthesis and its method are studied. Firstly, based on the construction of the virtual prototype model of the system, a comprehensive wearable comfort evaluation index considering the factors such as stress, deformation and the proportion of stress nodes was constructed. Secondly, based on the static simulation and evaluation index of system virtual prototype, multi-objective genetic optimization and local optimization synthesis of armor layer topology were carried out. Finally, the model reconstruction simulation data confirmed that the system had good wearing comfort. Our study provides a theoretical basis for the bearing performance and prototype construction of the subsequent wearable system.

Structural basis of the M-N protein interaction in a SARS-COV-2-related Betacoronavirus

The membrane (M) protein is the most abundant structural protein of coronaviruses including SARS-COV-2 and plays a central role in virus assembly through its interaction with various partner proteins. However, mechanistic details about how M protein interacts with others remain elusive due to lack of high-resolution structures. Here, we present the first crystal structure of a coronavirus M protein from Pipistrellus bat coronavirus HKU5 (batCOV5-M), which is closely related to SARS-COV-2 M protein. Furthermore, an interaction analysis indicates that the carboxy-terminus of the batCOV5 nucleocapsid (N) protein mediates its interaction with batCOV5-M. Combined with a computational docking analysis an M-N interaction model is proposed, providing insight into the mechanism of M protein-mediated protein interactions.

Mechanism of compound Fufangteng mixture-containing serum in promoting proliferation of bone marrow mesenchymal stem cell / 器官移植

Objective To investigate the effect of compound Fufangteng mixture-containing serum on the proliferation of bone marrow mesenchymal stem cell (BMSC) and its mechanism. Methods Rat BMSC were isolated, cultured and purified in vitro by direct adherence method. Cell morphology was observed. Surface markers were identified by flow cytometry. The rats were treated with compound Fufangteng mixture at a dose of 3 mL/(kg·d) by gavage for 14 d, and then the drug-containing serum was collected. BMSC were divided into the blank control group, drug-containing serum group, Notch1 small interfering ribonucleic acid (siRNA) group and Notch1 siRNA+drug-containing serum group. The proliferation rate of BMSC was detected and the relative expression levels of Notch1 signaling pathway-associated messenger ribonucleic acid (mRNA) and proteins were measured in each group. Results Microscopic observation showed that the first generation BMSC were seen in the long spindle shape, and grown in the parallel or spiral pattern. The third generation BMSC positively expressed CD90 and CD44, whereas were negative for CD45. Compared with the blank control group, the proliferation rate of BMSC in the drug-containing serum group and Notch1 siRNA+ drug-containing serum group was significantly increased, whereas that of BMSC was significantly decreased in the Notch1 siRNA group (all P < 0.05). Compared with the Notch1 siRNA group, the proliferation rate of BMSC was significantly increased in the Notch1 siRNA+drug-containing serum group (P < 0.05). Compared with the blank control group, the relative expression levels of Hey1 and Delta-like ligand (DLL)1 mRNA and proteins were significantly up-regulated in the drug-containing serum group, whereas those were significantly down-regulated in the Notch1 siRNA group and Notch1 siRNA+drug-containing serum group (all P < 0.05). Compared with the Notch1 siRNA group, the relative expression levels of Hey1 and DLL1 mRNA and proteins were significantly up-regulated in the Notch1 siRNA+drug-containing serum group (all P < 0.05). Conclusions Compound Fufangteng mixture-containing serum may promote the proliferation of rat BMSC, and its mechanism is probably associated with the activation of Notch1 signaling pathway.

Research progress on optimization strategies for microencapsulated islet transplantation / 器官移植

Islet transplantation is one of the effective therapies for diabetes mellitus. Nevertheless, multiple issues still exist, such as shortage of donors and adverse reactions caused by long-term use of immunosuppressants, which limit the islet survival post-transplantation. Microencapsulated islet transplantation may overcome these difficulties to certain extent, whereas many factors, such as the destruction of immune isolation microenvironment within the microcapsules and insufficient supply of oxygen and nutrients, constrain the application of microencapsulated islet transplantation in clinical practice. In recent years, how to enhance the effect of microencapsulated islet transplantation has been gradually studied. The application of stem cells in microencapsulated islet transplantation has steadily become a research hot spot. Therefore, the optimizing strategies for microencapsulated islet transplantation and the application of stem cells in microencapsulated islet transplantation were reviewed, and the potential improvement techniques of microencapsulated islet transplantation were investigated in this article, aiming to provide reference for further clinical application of microencapsulated islet transplantation.

Research status and prospect of basic application of islet organoid / 器官移植

Organoids are tissue structures, generated from pluripotent stem cells and cultured in vitro, which form self-organize and recapitulate tissues with similar structure and function to the original organs. Organoids have similar appearance and function to the original tissues, and have been widely applied in basic research and clinical trial. At present, the organoids of liver, kidney, islet, brain, intestine and other organs have been successfully cultivated. The use of islet organoid is a hotspot in the field of organoid research. However, islet organoid is currently applied in basic research because rejection after organ transplantation and other issues remain unresolved. In this article, the origin, development and basic application of islet organoid were reviewed, aiming to provide reference for the transformation from basic research of islet organoid into clinical application as well as the treatment of diabetes mellitus.

Epidemiological characteristics of influenza in Guangdong province, during winter of 2017-2018 / 中华流行病学杂志

Objective To understand the epidemiological characteristics of influenza in Guangdong province,during the winter of 2017-2018,to provide evidence for response to the diversity of influenza,in different seasonal patterns.Methods Data on weekly influenza surveillance from January 2016 to April 2018,were collected in Guangdong.Information on patients with Influenza-like illness (ILI),on influenza virus positive rates and on outbreaks during the winter of 2017 to 2018,was analyzed and compared with those in spring of 2016 and summer of 2017.x2 test and Fisher exact test were used.Results In the above said winter,the average percentage of visits for ILI in 28 hospitals where sentinel surveillance program had been set,was 4.99％ (157 235/3 149 656),which was above the level of the same period in the previous five years.The positive rates of influenza virus among samples collected from ILI outpatients and hospitalized cases under severe acute respiratory infection (SARI) were 28.33％ (2 137/7 543) and 14.93％ (256/1 715),with the proportions of B (Yamagata) as 70.43％ (1 505/2 137) and 73.05％ (187/256) respectively.A total of 257 influenza outbreaks were reported in the winter period,with 82.49％ (212/257) occurred in elementary schools.Cases aged 6-14 years occurred in winter and spring appeared of having higher positive rate than those seen in summer (P＜0.05) whereas elderly cases aged 60 and above showed higher positive rate in summer than those in winter and spring two seasons (P＜0.05).Conclusions Epidemiological characteristics of influenza appeared in Guangdong province,during the winter from 2017 to 2018,were correlated to Influenza B (Yamagata).Capacity on the implementation of surveillance programs and on the coverage of vaccination should be improved and increased in order to control influenza in different epidemic seasons,in Guangzhou.

Epidemiological characteristics of influenza in Guangdong province, during winter of 2017-2018 / 中华流行病学杂志

Objective To understand the epidemiological characteristics of influenza in Guangdong province,during the winter of 2017-2018,to provide evidence for response to the diversity of influenza,in different seasonal patterns.Methods Data on weekly influenza surveillance from January 2016 to April 2018,were collected in Guangdong.Information on patients with Influenza-like illness (ILI),on influenza virus positive rates and on outbreaks during the winter of 2017 to 2018,was analyzed and compared with those in spring of 2016 and summer of 2017.x2 test and Fisher exact test were used.Results In the above said winter,the average percentage of visits for ILI in 28 hospitals where sentinel surveillance program had been set,was 4.99％ (157 235/3 149 656),which was above the level of the same period in the previous five years.The positive rates of influenza virus among samples collected from ILI outpatients and hospitalized cases under severe acute respiratory infection (SARI) were 28.33％ (2 137/7 543) and 14.93％ (256/1 715),with the proportions of B (Yamagata) as 70.43％ (1 505/2 137) and 73.05％ (187/256) respectively.A total of 257 influenza outbreaks were reported in the winter period,with 82.49％ (212/257) occurred in elementary schools.Cases aged 6-14 years occurred in winter and spring appeared of having higher positive rate than those seen in summer (P＜0.05) whereas elderly cases aged 60 and above showed higher positive rate in summer than those in winter and spring two seasons (P＜0.05).Conclusions Epidemiological characteristics of influenza appeared in Guangdong province,during the winter from 2017 to 2018,were correlated to Influenza B (Yamagata).Capacity on the implementation of surveillance programs and on the coverage of vaccination should be improved and increased in order to control influenza in different epidemic seasons,in Guangzhou.

Value of urinary albumin/creatinine ratio for assessing coronary heart disease complicating thyroid dysfunction / 国际检验医学杂志

Objective To explore the value of urinary albumin/creatinine ratio (ACR) in coronary heart disease(CHD) compli-cating thyroid dysfunction and its correlation with the various detection indicators of thyroid function.Methods The results of uri-nary ACR and thyroid function detection in 863 patients with CHD in our hospital from November 2015 to August 2016 were col-lected.According to the standards of American National Kidney Foundation (NKF) and Food and Drug Administration(FDA) ,863 CHD patients were divided into the group A (ACR≤10.0 mg/g · Cr) ,B(10.0 mg/g · Cr300 mg/g · Cr).According to the reference values of thyroid functional indica-tors ,these patients were divided into the thyroid function normal and abnormal groups.Results The ACR level was negatively cor-related with the FT3 level in 863 CHD patients(r= -0.297 ,P10.0 mg/g · Cr and the patients with ACR ≤ 10.0 mg/g · Cr ,the difference was statistically significant (P10.0 mg/g · Cr in CHD patients.

Establishment of chronic myocardial ischemia model in minipigs and application of noninvasive telemetry technique / 中国比较医学杂志

In order to establish the minipig model of chronic myocardial ischemia and apply non-invasive telemetry technique, the minipig model of chronic myocardial ischemia was made induced by Vitamin D3, isoproterenol and combined with high fat diet, and the non-invasive telemetry technique was used to detect and evaluate the symptoms of minipig model of chronic myocardial ischemia.Moreover, the effects of transport stress and the risk factors of atherosclerosis (AS) induced by high fat diet among Wuzhishan minipigs, Bama minipigs and Tibetan minipigs were also evaluated.Our study has successful established the Bama minipig model of chronic myocardial ischemia and the technical specification for evaluation,.The non-invasive telemetry technique can be used to detect and evaluate the symptoms of chronic myocardial ischemia model, and defines minipigs at least need to keep for more than 4 weeks after transport stress to adaptive recovery period.In addition, the different characteristics of AS risk factors such as hyperlipidemia, hypertension and hyperinsulinemia were observed in Wuzhishan minipigs, Bama minipigs and Tibetan minipigs in high fat environment, and this provides a reference for the selection and application of minipigs in the research of cardiovascular diseases.

Effect of Tongsaimai Tablet on experimental atherosclerosis in rats / 中成药

AIM:To investigate the effect of TSM tablet on rat' s atherosclerotic model' s endothelial cell and explore the mechanism of it.METHODS:Fifty Wistar rats were randomly assigned into five groups:control group,model group,Simvastatin group,TSM high group,TSM low group.All groups were fed with high fat diet and vitamin D_3 except for control group to set up atherosclerosis model.After 12 weeks we detected circle endothelial cell,angiotensin Ⅱ and electron microscopy morphology of arteries.RESULTS:Level of circulating enthelia cell(CEC)and Ang Ⅱ in model rats were significantly higher.TSM can reduce level of the CEC and Ang Ⅱ.Model group rat' s artery endothelial cells were severely damaged under electron microscopy;rat's artery endothelial cells in TSM group were basically intact and its internal elastic membrane was unbroken on it thickness was even,without significant lesion.CONCLUSION:TSM by reducing the number of CEC,the level of Ang Ⅱ used for experimental atherosclerotic endothelial cell in rats has the protective effect.

Effect of Tongsaimai Tablet on experimental atherosclerosis in rats / 中成药

AIM:To investigate the effect of TSM tablet on rat's atherosclerotic model's endothelial cell and explore the mechanism of it.METHODS:Fifty Wistar rats were randomly assigned into five groups:control group,model group,Simvastatin group,TSM high group,TSM low group.All groups were fed with high fat diet and vitamin D3 except for control group to set up atherosclerosis model.After 12 weeks we detected circle endothelial cell,angiotensinⅡ and electron microscopy morphology of arteries.RESULTS:Level of circulating enthelia cell(CEC) and AngⅡin model rats were significantly higher.TSM can reduce level of the CEC and AngⅡ.Model group rat's artery endothelial cells were severely damaged under electron microscopy;rat's artery endothelial cellsin TSM group were basically intact and its internal elastic membrane was unbroken on it thickness was even,without significant lesion.CONCLUSION:TSM by reducing the number of CEC,the level of AngⅡ used for experimental atherosclerotic endothelial cell in rats has the protective effect.