Umbilical cord mesenchymal stem cells in ulcerative colitis treatment: efficacy and possible mechanisms.

BACKGROUND: Mesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms. METHODS: This prospective, self-controlled clinical study was conducted at Henan Provincial People's Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation. RESULTS: Forty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1ß, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy. CONCLUSION: UMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines. TRIAL REGISTRATION: The study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.

The Different Influence of Cutibacterium Acnes and Staphylococcus Epidermidis in the Lumbar Disc: An in Vivo Study in Rabbits.

STUDY DESIGN: Animal laboratory study. OBJECTIVE: This study investigated the effects of C. acnes and S. epidermidis on the lumbar discs of rabbits, as well as the outcomes of combined infection. SUMMARY OF BACKGROUND DATA: Many studies have indicated that bacterial infections are associated with lumbar disc degeneration (LDD). The most commonly cultured bacteria from disc tissues are Cutibacterium acne (C. acnes) and Staphylococcus epidermidis (S. epidermidis). METHODS: New Zealand white rabbits (n=40) were randomly divided into control, C. acnes, S. epidermidis, and C. acnes plus S. epidermidis (i.e., combined) groups. All groups except the control were injected with 25 µL of saline at L4-L5 and 25 µL of bacteria (1×107 CFU/mL) at L5-L6. All injections were performed under X-ray guidance. Weight measurements, haematological evaluations, and magnetic resonance imaging were performed after 4, 8, and 12 weeks. Histological examination and gene expression detection were performed 12 weeks after surgery. RESULTS: Inflammatory factors in the blood and weight did not differ among the groups after 4, 8, and 12 weeks (P >0.05). However, after 4 weeks, LDD occurred in the C. acnes group, and discitis occurred in the S. epidermidis and combined groups, all of which worsened after 8 weeks. After 12 weeks, the nucleus pulposus (NP) protruded and compressed the spinal cord in the C. acnes group, and tissue staining showed decreased NP tissue and cartilaginous endplate fracture. In the S. epidermidis and combined groups, the discitis was more confined, but tissue staining revealed a significant decrease in NP tissue, and loss of the normal disc structure. CONCLUSIONS: In the early stage of infection in rabbits, C. acnes caused LDD, and S. epidermidis caused discitis. Co-infection with C. acnes and S. epidermidis caused discitis but was more limited in scope than infection with S. epidermidis alone.

Dencichine/palygorskite nanocomposite incorporated chitosan/polyvinylpyrrolidone film for accelerating wound hemostasis.

The development of efficient, safe, environmentally friendly, and user-friendly hemostatic dressings remains a great challenge for researchers. A variety of clay minerals and plant extracts have garnered considerable attention due to their outstanding hemostatic efficacy and favorable biosafety. In this study, a facile solution casting strategy was employed to prepare nanocomposite films by incorporating natural nanorod-like palygorskite (Pal) and herb-derived hemostat dencichine (DC) based on chitosan and polyvinylpyrrolidone. The dynamic blood clotting index demonstrated that the nanocomposite film with a DC addition of 1.0 wt% exhibited significantly superior hemostatic properties compared to both pure DC powder or commercial hemostatic agent Yunnan Baiyao. This improvement was primarily attributed to proper blood affinity, increased porosity, enhanced adhesion of platelets and erythrocytes, as well as the accelerated activation of coagulation factors and platelets. Under the synergistic effect of Pal and DC, the nanocomposite film displayed suitable tensile strength (20.58 MPa) and elongation at break (47.29 %), which may be due to the strong intermolecular hydrogen bonding and electrostatic interaction between Pal/DC and macropolymers. Notably, the nanocomposite film exhibited remarkable antibacterial effectiveness and desirable cytocompatibility, as well as the capability of promoting wound healing in vitro. Taken together, the nanocomposite film synergized with Pal and DC is expected to be an efficacious and suitable wound dressing.

Development and validation of a nomogram for pneumonia risk in burn patients with inhalation injury: a multicenter retrospective cohort study.

BACKGROUND: Burn patients with inhalation injury are at higher risk of developing pneumonia, and yet there is no reliable tool for the assessment of the risk for such patients at admission. This study aims to establish a predictive model for pneumonia risk for burn patients with inhalation injury based on clinical findings and laboratory tests. METHOD: This retrospective study enrolled 546 burn patients with inhalation injury. They were grouped into a training cohort and a validation cohort. The least absolute shrinkage and selection operator (LASSO) regression analysis and binary logistic regression analysis were utilized to identify risk factors for pneumonia. Based on the factors, a nomogram for predicting pneumonia in burn patients with inhalation injury was constructed. Areas under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA) were used to evaluate the efficiency of the nomogram in both the training and validation cohorts. RESULTS: The training cohort included 432 patients, and the validation cohort included 114 patients, with a total of 225 (41.2%) patients experiencing pneumonia. Inhalation injury, tracheal intubation/tracheostomy, low serum albumin, and high blood glucose were independent risk factors for pneumonia in burn patients with inhalation injury and they were further used to build the nomogram. The AUC of the nomogram in the training and validation cohorts were 0.938 (95% CI: 0.917-0.960) and 0.966 (95% CI: 0.931-1), respectively. The calibration curve for probability of pneumonia showed optimal agreement between the prediction by nomogram and the actual observation, and the DCA indicated that the constructed nomogram conferred high clinical net benefit. CONCLUSION: This nomogram can accurately predict the risk of developing pneumonia for burn patients with inhalation injury, and help professionals to identify high-risk patients at an early stage as well as to make informed clinical decisions.

[Effect of aerobic exercise on AKT/GSK3ß mediated hepatocyte apoptosis in nonalcoholic fatty liver disease].

OBJECTIVE: To investigate the effect of aerobic exercise on AKT/GSK3ß pathway-mediated hepatocyte apoptosis in non-alcoholic fatty liver diseases(NAFLD). METHODS: A total of 30 6-week-old male C57BL/6J mice, and mice were fed adaptively for one week. The control group was fed with ordinary diet, and the model group and model exercise group were fed with high-fat diet until 18 weeks. At the 10th week of the experiment, the model exercise group received aerobic exercise intervention for 8 consecutive weeks until the end of the experiment at the 18th week. Automatic biochemical analyzer to detect serum total cholesterol(TC), triglycerides(TG), alanine aminotransferase(ALT), aspartate aminotransferase(AST), low-density lipoprotein(LDL-C) and high-density lipoprotein(HDL-C) levels. Liver pathological morphology was observed by staining with oil red O and HE. The expression changes of AKT, P-AKT~( Ser473), GSK3ß, P-GSK3ß~(Ser9) and Caspase-3 proteins were detected by western blot, and the apoptosis of hepatocytes was detected by in situ terminal transferase labeling(TUNEL). RESULTS: (1) After intervention, compared with control group, body weight, liver index, serum TC, TG, ALT, AST and LDL-C levels in model group were significantly increased(P<0.01 or P<0.05), while HDL-C level was significantly decreased(P<0.01). Compared with model group, body weight, liver index, serum TC, TG, ALT, AST and LDL-C levels in model exercise group were significantly decreased(P<0.01 or P<0.05), while HDL-C level was significantly increased(P<0.01). (2) Compared with the control group, hepatocyte steatosis and the number of lipid droplets in model group were significantly increased. Compared with the model group, the degree of hepatic adipose degeneration was significantly improved and the number of hepatic lipid droplets was significantly decreased in the model exercise group. (3) Compared with control group, the protein expression levels of P-AKT~(Ser473) and P-GSK3ß~(Ser9) in model group were significantly decreased(P<0.01 or P<0.05), the protein expression levels of Caspase-3 were significantly increased(P<0.05), and the number of hepatocyte apoptosis was significantly increased(P<0.05). Compared with model group, the expression of P-AKT~(Ser473) and P-GSK3ß~(Ser9) protein in model exercise group was significantly increased(P<0.01 or P<0.05), the expression of Caspase-3 protein was significantly decreased(P<0.05), and the number of hepatocyte apoptosis was significantly decreased(P<0.01). CONCLUSION: Aerobic exercise can effectively improve NAFLD, by activating AKT/GSK3ß pathway and increasing the expression of AKT/GSK3ß pathway related molecules, thereby reducing caspase-3 expression and hepatocyte apoptosis.

Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling Pathway.

BACKGROUND: The prevalence of obesity, as well as obesity-induced chronic inflammatory diseases, is increasing worldwide. Chronic inflammation is related to the complex process of angiogenesis, and we found that adipose-derived stem cells from obese subjects (obADSCs) had proangiogenic features, including higher expression levels of interleukin-6 (IL-6), Notch ligands and receptors, and proangiogenic cytokines, than those from control subjects. We hypothesized that IL-6 and Notch signaling pathways are essential for regulating the proangiogenic characteristics of obADSCs. OBJECTIVE: This study aimed to investigate whether the inflammatory cytokine interleukin 6 (IL-6) promotes the proangiogenic capacity of adipose stem cells in obese subjects via the IL-6 signaling pathway. METHODS: We compared the phenotype analysis as well as cell doubling time, proliferation, migration, differentiation, and proangiogenic properties of ADSCs in vitro. Moreover, we used small interfering RNAs to inhibit the gene and protein expression of IL-6. RESULTS: We found that ADSCs isolated from control individuals (chADSCs) and obADSCs had similar phenotypes and growth characteristics, and chADSCs had a stronger differentiation ability than obADSCs. However, obADSCs were more potent in promoting EA.hy926 cell migration and tube formation than chADSCs in vitro. We confirmed that IL-6 siRNA significantly reduced the transcriptional level of IL-6 in obADSCs, thereby reducing the expression of vascular endothelial growth factor (VEGF)- A, VEGF receptor 2, transforming growth factor ß, and Notch ligands and receptors in obADSCs. CONCLUSION: The finding suggests that inflammatory cytokine interleukin-6 (IL-6) promotes the proangiogenic ability of obADSCs via the IL-6 signaling pathway.

DRR1 promotes neuroblastoma cell differentiation by regulating CREB expression.

BACKGROUND: Neuroblastoma is the most common cancer in infants and the most common extracranial solid tumor in childhood. DRR1 was identified to be downregulated in poorly differentiated ganglion cells from neuroblastoma model mice. However, the roles of DRR1 in neuroblastoma remain largely unclear. METHODS: The neuroblastoma cells were induced to differentiate, and the expression of DRR1 was detected. The expression of the neuroblastoma cell differentiation markers was analyzed in DRR1 shRNA- or DRR1-expressing vector-treated neuroblastoma cells. The downstream genes of DRR1 were screened with ChIP-seq assay. Finally, TNB1 cells were infected with DRR1 shRNA and CREB expressing vector containing lentivirus, and the expression of the cell differentiation markers, cell cycle distribution and tumor growth were analyzed. RESULTS: The expression of DRR1 was increased in differentiated neuroblastoma cells, and downregulation of DRR1 expression inhibited the differentiation of neuroblastoma cells. Further experiments indicated that CREB is a candidate downstream gene of DRR1, and it mediates neuroblastoma cell differentiation. Moreover, overexpression of CREB rescued the effect of DRR1 shRNA on cell differentiation, cell cycle distribution and tumor growth in neuroblastoma. CONCLUSIONS: DRR1-CREB axis modulates the differentiation of neuroblastoma cells and is associated with the outcome of neuroblastoma patients. IMPACT: DRR1 is involved in regulation of the differentiation of neuroblastoma. Binding with actin is essential for DRR1 to regulate neuroblastoma cell differentiation. CREB is a candidate downstream gene of DRR1 in regulating of the differentiation of neuroblastoma.

Study on the Reaction Mechanism of Ethylene Propylene Diene Monomer Sealing Material and C5F10O-CO2 Gas Mixture.

The eco-friendly insulating medium C5F10O gas has attracted the attention of many researchers due to its superior environmental protection and insulation properties. However, there are few studies on the compatibility of C5F10O gas with sealing materials for the gas-insulated equipment (GIE), which will bury hidden dangers for its engineering application. In this study, the compatibility of C5F10O gas with an ethylene propylene diene monomer (EPDM) sealing material which is most used in equipment was tested, and its reaction mechanism was simulated. The study found that the O element on the carbonyl group of C5F10O gas has high chemical reactivity and will interact with EPDM rubber. During the interaction process, EPDM rubber will also react with the C3F6 gas generated by the decomposition of C5F10O gas, and at the same time, it will also decompose C5F10O gas to produce more C3F6O and C3HF7. The surface of EPDM rubber will produce oily substances and a large number of crystal particles, which will cause its mechanical properties to deteriorate and shorten its service life. Therefore, it is necessary to carry out anti-corrosion treatment on the surface of EPDM rubber or replace the sealing material with better compatibility when designing and manufacturing GIE.

Frequent injections of high-dose human umbilical cord mesenchymal stem cells slightly aggravate arthritis and skeletal muscle cachexia in collagen-induced arthritic mice.

A single injection of low-dose human umbilical cord-derived mesenchymal stem cells (UC-MSCs) has been previously demonstrated to relieve synovitis and bone erosion in animal models of arthritis, but whether frequent injections of high-dose UC-MSCs relieve arthritis and inhibit loss of muscle mass has remained elusive. In the present study, DBA/1 mice were randomly divided into three groups: Normal (wild-type mice; n=11), collagen-induced arthritis (CIA; n=12) and CIA treated with UC-MSCs (n=11; 5x106 UC-MSCs per week for 3 weeks). Arthritis and skeletal muscle cachexia were evaluated until the end of the experiment on day 84. It was indicated that both the CIA and UC-MSC groups had lower body weights compared with the normal mice. Clinical arthritis scores, hind ankle diameters, synovitis and bone erosion progressively increased and were similar between the CIA and UC-MSC groups. Although there was no difference in food intake among the three groups, the normalized food intake of normal group was significantly higher than CIA group and UC-MSC group from day 42 onwards; there was no significance on day 77 but this could be neglected. Furthermore, gastrocnemius muscle weight in the UC-MSC group was significantly reduced compared with that in the CIA and normal groups. The UC-MSC group had higher levels of proinflammatory cytokines, such as TNF-α, IL-6 and IL-1ß than those in the CIA group. However, the other cytokines assessed and the fibrosis indices in the CIA and UC-MSC groups were not different from those in the control group and there was no inflammatory cell infiltration. Thus, frequent injections of high-dose UC-MSCs slightly aggravated synovitis and muscle cachexia in the murine CIA model and should therefore be avoided in the treatment of arthritis.

Human mesenchymal stem cells treatment improved hepatic lesions and reversed gut microbiome disorder in non-alcoholic steatohepatitis.

Effective therapies for non-alcoholic steatohepatitis (NASH) are urgently needed. We investigated the effect of human mesenchymal stem cells (hMSCs) on the intestinal flora in NASH treatment. We isolated the hMSCs from the umbilical cords and divided male C57BL/6 mice into three groups, namely, chow, methionine-choline-deficient (MCD), and MCD+hMSCs. After collecting the feces and liver of the mice, we evaluated the histological changes in the liver and measured the inflammatory and fibrogenesis cytokines. Fecal microbiome and metabolome were analyzed using 16S rRNA gene sequencing analyses. The hMSCs treatment could alleviate hepatic steatosis, inflammation and fibrosis induced by MCD diet. It could also reverse the microbiome and metabolome disorders in the NASH model. Correlation analysis of the interaction among bacteria amplified the effects of the bacteria in host. In conclusion, hMSCs treatment could improve NASH-related lesions and reverse gut microbiome and metabolome disorder in NASH.

Comparison of the biological characteristics of umbilical cord mesenchymal stem cells derived from the human heterosexual twins.

Mesenchymal stromal/stem cells (MSCs) are attracting more and more attention due to their tissue regenerative properties and immunomodulatory functions. MSCs may be the most acceptable, safe, and effective source for allogeneic cell therapy, and have been used in medical treatment. However, the similarities and differences between umbilical cord-derived MSCs (UC-MSCs) of heterosexual twins remain poorly understood. In this study, we compared the biological characteristics of UC-MSCs of heterosexual twins in vitro. We found that male fetal UC-MSCs and female fetal UC-MSCs share a similar phenotype and multi-lineage differentiation potential, and male fetal UC-MSCs show a significantly higher proliferation and adipogenic ability than female fetal UC-MSCs. UC-MSCs from heterosexual twins showed significant differences in the expression levels of NANOG, OCT4, TERT, and SOX2. In addition, male MSCs are more potent in the expression of inflammatory cytokines to lipopolysaccharide (LPS)-induced inflammation. In future clinical applications using MSCs for inflammation-related diseases, these biological characteristics differences with different genders will guide our clinical methods.

Interaction Mechanism between the C4F7N-CO2 Gas Mixture and the EPDM Seal Ring.

C4F7N (fluorinated nitrile) has been introduced as a remarkable substitute gas for the greenhouse gas SF6 (sulfur hexafluoride) which is used in gas-insulated equipment (GIE). Intensive investigations about the compatibility between C4F7N and materials used in GIE are required to decide their long-term behavior. In this paper, the interaction mechanism between EPDM, used as a sealing ring in GIE, and C4F7N-CO2 was explored. The composition and morphology properties of EPDM were first revealed based on scanning electron microscopy and X-ray photoelectron spectroscopy. It was found that EPDM rubber is incompatible with the C4F7N-CO2 gas mixture at temperatures higher than 70 °C. There exist chemical reactions between EPDM and C4F7N, resulting in the generation of gaseous byproducts including C3F6, CF3H, and C2F5H and corrosion of EPDM. DFT calculation also shows that the interaction between C4F7N and EPDM could cause the dissociation of C4F7N. Relevant results provide important guidance for the engineering application of the C4F7N gas mixture.

Exosomal proteome from the serum, bone marrow, and palm and toe pustular skin tissues of a single patient with SAPHO syndrome.

Exosome proteomic analysis may reveal differentially abundant proteins that are of significance for clarifying the pathogenesis of SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) syndrome. Exosomes were isolated from the serum, bone marrow and skin tissue of the palm and toe pustular areas in a unique patient with SAPHO syndrome. The exosomes were not different from those of healthy subjects in size (114.1 ± 73.7 nm) or morphology. Label-free exosome proteomic analysis identified 198 more abundant proteins and 183 less abundant compared with those of healthy subjects. Gene ontology enrichment analysis revealed that these proteins were involved in binding with a variety of biological molecules and participated in biological processes related to autoimmunity or inflammation. A total of 243 KEGG (Kyoto Encyclopedia of Gene and Genomes) pathways were enriched, of which 43 were related to immune function. It was speculated that five differentially abundant proteins, Mitogen-activated protein kinase 1 (MAPK1/MK01), Tyrosine protein kinase (SYK), Integrin beta-3 (ITB3), Serine/threonine-protein phosphatase 2a catalytic subunit alpha isoform (PP2AA) and Serine/threonine-protein phosphatase 2a 65 kDa regulatory subunit A beta isoform (2AAB), associated with multiple KEGG pathways, forms an interaction network that may be involved in the occurrence, development and prognosis of SAPHO syndrome. SIGNIFICANCE: Exosomes of SAPHO syndrome patient were not significantly different from those of healthy subjects in size and morphology. Label-free proteomic analysis of exosomal proteins in patient with SAPHO syndrome speculated 5 proteins MAPK1, SYK, ITB3, PP2AA and 2AAB, which may be involved in the occurrence, development and prognosis of SAPHO syndrome by binding with other biological molecules. It is speculated for the first time that proteins Histone H2A type 1-J and Histone H4 were related to SAPHO syndrome. Clinic relevance. Exosome proteomics can suggest novel pathological data in patients with SAPHO.

Effect of oxygen on power frequency breakdown voltage and decomposition characteristics of the C5F10O/N2/O2 gas mixture.

Sulfur hexafluoride (SF6) is widely used in the power industry because of its excellent insulation and arc extinguishing performance; however, as the global environment is deteriorating, the need to replace SF6 is becoming significantly critical. In recent years, C5F10O has received extensive attention as a potential alternative to SF6. In this study, a part of N2 in C5F10O/N2 was replaced by O2, and the breakdown voltages of C5F10O/N2/O2 at different oxygen concentrations under a slightly uneven electric field were tested. The dispersion of breakdown voltage and the discharge decomposition components of C5F10O/N2/O2 with different oxygen concentrations were analysed. It was found that as the oxygen concentration increased, the breakdown voltage of C5F10O/N2/O2 with 15 kPa C5F10O at 0.2 MPa increased, and the dispersion of the breakdown voltage became worse. When 0.5% O2 or more O2 was added to the C5F10O/N2 gas mixture, the carbon precipitates on the electrode surface disappeared. As the oxygen concentration continued to increase, another characteristic component, CF2O, could be detected, whereas C2F4 and C3F6 disappeared. It is believed that O2 can inhibit the formation of C2F6, C3F8, C4F10, and C3F7H. Therefore, it is recommended to use oxygen as the second buffer gas for the engineering applications of C5F10O. Moreover, the ratio of C5F10O to O2 is recommended to be 1 : 1.