Human Gingiva-Derived Mesenchymal Stromal Cells Attenuate Contact Hypersensitivity via Prostaglandin E2- Dependent Mechanisms

The immunomodulatory and anti-inflammatory functions of mesenchymal stromal cells (MSCs) have been demonstrated in several autoimmune/inflammatory disease models, but their contribution to the mitigation of contact hypersensitivity (CHS) remains unclear. Here, we report a new immunological approach using human gingiva-derived MSCs (GMSCs) to desensitize and suppress CHS and the underlying mechanisms. Our results showed that systemic infusion of GMSCs before the sensitization and challenge phase dramatically suppress CHS, manifested as a decreased infiltration of dendritic cells (DCs), CD8 + T cells, T H-17 and mast cells (MCs), a suppression of a variety of inflammatory cytokines, and a reciprocal increased infiltration of regulatory T cells and expression of IL-10 at the regional lymph nodes and the allergic contact areas. The GMSC-mediated immunosuppressive effects and mitigation of CHS were significantly abrogated on pretreatment with indomethacin, an inhibitor of cyclooxygenases. Under coculture condition of direct cell-cell contact or via transwell system, GMSCs were capable of direct suppression of differentiation of DCs and phorbol 12-myristate 13-acetate-stimulated activation of MCs, whereas the inhibitory effects were attenuated by indomethacin. Mechanistically, GMSC-induced blockage of de novo synthesis of proinflammatory cytokines by MCs is mediated partly by the tumor necrosis factor-alpha/prostaglandin E 2 (PGE 2) feedback axis. These results demonstrate that GMSCs are capable of desensitizing allergic contact dermatitis via PGE 2-dependent mechanisms. © AlphaMed Press

Peripheral primitive neuroectodermal tumor of the ovary with torsion

AbstractPeripheral primitive neuroectodermal tumors (pPNETs) of the ovary are rare monophasic teratomas, and fewer than 100 cases have been reported in the literature. pPNETs mainly involve young women during their reproductive age, therefore, accurate diagnosis followed by multimodal treatment should be taken into consideration for fertility preservation. We report a patient with stage IA pPNET of the ovary presenting with acute abdominal pain secondary to torsion that was successfully managed by fertility-sparing surgery and six courses of combination chemotherapy with vincristine, Adriamycin, and cyclophosphamide. She has had a disease-free survival of >3 years. This brief review demonstrates the clinical course of pPNET and summarizes the literature to show that clinical stage at the time of diagnosis is the most important prognostic factor and that the vast majority of recurrences are observed within 10 years

Docosahexaenoic acid has influence on action potentials and transient outward potassium currents of ventricular myocytes

<p>Abstract</p> <p>Background</p> <p>There are many reports about the anti-arrhythmic effects of ω-3 polyunsaturated fatty acids, however, the mechanisms are still not completely delineated. The purpose of this study was to investigate the characteristics of action potentials and transient outward potassium currents (I_to) of Sprague-Dawley rat ventricular myocytes and the effects of docosahexaenoic acid (DHA) on action potentials and I_to.</p> <p>Methods</p> <p>The calcium-tolerant rat ventricular myocytes were isolated by enzyme digestion. Action potentials and I_toof epicardial, mid-cardial and endocardial ventricular myocytes were recorded by whole-cell patch clamp technique.</p> <p>Results</p> <p><b>1.</b> Action potential durations (APDs) were prolonged from epicardial to endocardial ventricular myocytes (<it>P </it>< 0.05). <b>2.</b> I_tocurrent densities were decreased from epicardial to endocardial ventricular myocytes, which were 59.50 ± 15.99 pA/pF, 29.15 ± 5.53 pA/pF, and 12.29 ± 3.62 pA/pF, respectively at +70 mV test potential (<it>P </it>< 0.05). <b>3.</b> APDs were gradually prolonged with the increase of DHA concentrations from 1 μmol/L to 100 μmol/L, however, APDs changes were not significant as DHA concentrations were in the range of 0 μmol/L to 1 μmol/L. <b>4.</b> I_tocurrents were gradually reduced with the increase of DHA concentrations from 1 μmol/L to 100 μmol/L, and its half-inhibited concentration was 5.3 μmol/L. The results showed that there were regional differences in the distribution of action potentials and I_toin rat epicardial, mid-cardial and endocardial ventricular myocytes. APDs were prolonged and I_tocurrent densities were gradually reduced with the increase of DHA concentrations.</p> <p>Conclusion</p> <p>The anti-arrhythmia mechanisms of DHA are complex, however, the effects of DHA on action potentials and I_tomay be one of the important causes.</p

Comparative Geochemistry of 234Th, 210Pb, and 210Po: A Case Study in the Hung-Tsai Trough off Southwestern Taiwan

Detailed profiles of dissolved and particulate 234Th, 210Pb, and 210Po activities at three stations in the Hung-Tsai Trough off south western Taiwan were determined. The total 234Th activ ity is 20 ~ 25% deficientfrom its secular equilibrium in the entire water column. Except for an evident excess of 210Po at some depths in the mixed layer and in the pycnocline layer, total 210Po activity is also lower than total 210Pb activity. As a result of atmospheric deposition, 210Pb is about 25% in excess of its parent, 226Ra, through out the water column of the Hung-Tsai Trough. The ratios of the distribution coefficients of 234Th, 210Pb, and 210Po show that the order of particle affinity is Po > Th ~ Pb in the mixed layer and bottom layer, whereas the order changes, due to particlere generation, into Th > Pb > Po in the pycnocline layer of the Hung-Tsai Trough

Human Gingiva-Derived Mesenchymal Stem Cells Elicit Polarization of M2 Macrophages and Enhance Cutaneous Wound Healing

Increasing evidence has supported the important role of mesenchymal stem cells (MSCs) in wound healing, however, the underlying mechanism remains unclear. Recently, we have isolated a unique population of MSCs from human gingiva (GMSCs) with similar stem cell-like properties, immunosuppressive, and anti-inflammatory functions as human bone marrow-derived MSCs (BMSCs). We describe here the interplay between GMSCs and macrophages and the potential relevance in skin wound healing. When cocultured with GMSCs, macrophages acquired an anti-inflammatory M2 phenotype characterized by an increased expression of mannose receptor (MR; CD206) and secretory cytokines interleukin (IL)-10 and IL-6, a suppressed production of tumor necrosis factor (TNF)-α, and decreased ability to induce Th-17 cell expansion. In vivo, we demonstrated that systemically infused GMSCs could home to the wound site in a tight spatial interaction with host macrophages, promoted them toward M2 polarization, and significantly enhanced wound repair. Mechanistically, GMSC treatment mitigated local inflammation mediated by a suppressed infiltration of inflammatory cells and production of IL-6 and TNF-α, and an increased expression of IL-10. The GMSC-induced suppression of TNF-α secretion by macrophages appears to correlate with impaired activation of NFκB p50. These findings provide first evidence that GMSCs are capable to elicit M2 polarization of macrophages, which might contribute to a marked acceleration of wound healing. © AlphaMed Press

HbA1C Variability Is Strongly Associated With the Severity of Peripheral Neuropathy in Patients With Type 2 Diabetes

Variability in HbA1c is associated with a higher risk of cardiovascular disease and microvascular complications in patients with type 2 diabetes. The present study evaluated the severity of somatic nerve dysfunction at different stages of chronic glycemic impairment, and its correlation with different cardio-metabolic parameters. The study was conducted on 223 patients with type 2 diabetes. We calculated the intrapersonal mean, standard deviation (SD), and coefficient of variation of HbA1c for each patient using all measurements obtained for 3 years prior to the study. Patients were divided into quartiles according to the SD of HbA1c, and we constructed composite scores of nerve conduction as the severity of peripheral neuropathy. Linear regression analysis was performed to evaluate the influence of independent variables on mean composite scores. Those with higher SD-HbA1c had a higher body mass index, mean and index HbA1c, triglyceride and uric acid level, urinary albumin excretion and albumin-creatinine ratio, proportion of insulin therapy, and prevalence of hypertension as the underlying diseases, but lower estimate glomerular filtration rate (eGFR). In addition, those with higher SD-HbA1c showed lower amplitudes and reduced motor nerve conduction velocity in tested nerves, and lower sensory nerve conduction velocity in the sural nerve. Furthermore, those with higher SD-HbA1c had higher composite scores of low extremities. Multiple linear regression analysis revealed that diabetes duration, SD-HbA1c, and eGFR were independently associated with mean composite scores. Based on our results, HbA1c variability plus chronic glycemic impairment is strongly associated with the severity of peripheral neuropathy in patients with type 2 diabetes. Aggressively control blood glucose to an acceptable range and avoid blood glucose fluctuations by individualized treatment to prevent further nerve damage

HbA1C Variability Is Strongly Associated With the Severity of Cardiovascular Autonomic Neuropathy in Patients With Type 2 Diabetes After Longer Diabetes Duration

BackgroundVariability in the glycated hemoglobin (HbA1c) level is associated with a higher risk of microvascular complications in patients with type 2 diabetes. We tested the hypothesis that HbA1c variability is not only strongly associated with the presence but also the degree of severity of cardiovascular autonomic neuropathy (CAN) in patients with long diabetes durations (more than 10 years).MethodsFor each patient, the intrapersonal mean, standard deviation (SD), and coefficient of variation (CV) for HbA1c were calculated using all measurements obtained 3 years before the study. We constructed the composite autonomic scoring scale (CASS) as a measure of the severity of cardiovascular autonomic functions. Stepwise logistic regression and linear regression analyses were performed to evaluate the presence of CAN and the influence of independent variables on the mean CASS, respectively.ResultsThose with CAN had a higher mean age, a higher low-density lipoprotein cholesterol (LDL-C), HbA1c-SD, HbA1c-CV, mean HbA1c, and index HbA1c, higher prevalence of retinopathy as the underlying disease, and lower high-density lipoprotein (HDL) levels. Stepwise logistic regression showed that HbA1c-SD and retinopathy were risk factors that were independently associated with the presence of CAN. Mean HbA1c, HbA1c-CV, HbA1c-SD, and index HbA1c were positively correlated with mean CASS, and a multiple linear regression analysis revealed that HbA1c-SD was independently associated with the mean CASS.ConclusionHbA1c variability is strongly associated with not only the presence but also the degree of severity of CAN. A longitudinal study is required to confirm whether controlling blood glucose level is effective in reducing CAN progression

Role of Mesenchymal Stem Cells on Cornea Wound Healing Induced by Acute Alkali Burn

The aim of this study was to investigate the effects of subconjunctivally administered mesenchymal stem cells (MSCs) on corneal wound healing in the acute stage of an alkali burn. A corneal alkali burn model was generated by placing a piece of 3-mm diameter filter paper soaked in NaOH on the right eye of 48 Sprague-Dawley female rats. 24 rats were administered a subconjunctival injection of a suspension of 2×106 MSCs in 0.1 ml phosphate-buffered saline (PBS) on day 0 and day 3 after the corneal alkali burn. The other 24 rats were administered a subconjunctival injection of an equal amount of PBS as a control. Deficiencies of the corneal epithelium and the area of corneal neovascularization (CNV) were evaluated on days 3 and 7 after the corneal alkali burn. Infiltrated CD68+ cells were detected by immunofluorescence staining. The mRNA expression levels of macrophage inflammatory protein-1 alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) were analyzed using real-time polymerase chain reaction (real-time PCR). In addition, VEGF protein levels were analyzed using an enzyme-linked immunosorbent assay (ELISA). MSCs significantly enhanced the recovery of the corneal epithelium and decreased the CNV area compared with the control group. On day 7, the quantity of infiltrated CD68+ cells was significantly lower in the MSC group and the mRNA levels of MIP-1α, TNF-α, and VEGF and the protein levels of VEGF were also down-regulated. However, the expression of MCP-1 was not different between the two groups. Our results suggest that subconjunctival injection of MSCs significantly accelerates corneal wound healing, attenuates inflammation and reduces CNV in alkaline-burned corneas; these effects were found to be related to a reduction of infiltrated CD68+ cells and the down-regulation of MIP-1α, TNF-α and VEGF

De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge