The Reduction of Peripheral Blood CD4+ T Cell Indicates Persistent Organ Failure in Acute Pancreatitis

ObjectiveFew data are available on the potential role of inflammatory mediators and T lymphocytes in persistent organ failure (POF) in acute pancreatitis (AP). We conducted a retrospective study to characterize their role in the progression of POF in AP.MethodsA total of 69 AP patients presented within 24 hours from symptom onset developing organ failure (OF) on admission were included in our study. There were 39 patients suffering from POF and 30 from transient OF (TOF). On the 1st, 3rd and 7th days after admission, blood samples were collected for biochemical concentration monitoring including serum IL-1β, IL-6, TNF-α and high-sensitivity C-reactive protein (hs-CRP). The proportions of peripheral CD4⁺ and CD8⁺ T lymphocytes were assessed based on flow cytometry simultaneously.ResultsPatients with POF showed a significantly higher value of IL-1β and hs-CRP on day 7 compared with the group of TOF (P < 0.05). Proportions of CD4⁺ T cells on days 1, 3, 7 and CD4⁺ / CD8⁺ ratio on day 1 were statistically lower in the group of POF patients (P < 0.05). A CD4⁺ T cell proportion of 30.34% on day 1 predicted POF with an area under the curve (AUC) of 0.798, a sensitivity with 61.54% and specificity with 90.00%, respectively.ConclusionsThe reduction of peripheral blood CD4⁺ T lymphocytes is associated with POF in AP, and may act as a potential predictor.     

Thermal Modelling Analysis of Spiral Wound Supercapacitor under Constant-Current Cycling

A three-dimensional modelling approach is used to study the effects of operating and ambient conditions on the thermal behaviour of the spiral wound supercapacitor. The transient temperature distribution during cycling is obtained by using the finite element method with an implicit predictor-multicorrector algorithm. At the constant current of 2A, the results show that the maximum temperature appears in core area. After 5 cycles, the maximum temperature is 34.5°C, while in steady state, it’s up to 42.5°C. This paper further studies the relationship between the maximum temperature and charge-discharge current. The maximum temperature will be more than 60°C after 5 cycles at the current of 4A, and cooling measurements should be taken at that time. It can provide thoughts on inner temperature field distribution and structure design of the spiral wound supercapacitor in working process.     

A Self-microemulsifying Drug Delivery System (SMEDDS) for a Novel Medicative Compound Against Depression: a Preparation and Bioavailability Study in Rats

AJS is the code name of an untitled novel medicative compound synthesized by the Tasly Holding Group Company (Tianjin, China) based on the structure of cinnamamide, which is one of the Biopharmaceutics Classification System (BCS) class II drugs. The drug has better antidepressant effect, achieved by acting on the 5-hydroxytryptamine receptor. However, the therapeutic effects of the drug are compromised due to its poor water solubility and lower bioavailability. Herein, a self-microemulsifying drug delivery system (SMEDDS) was developed to improve its solubility and oral bioavailability. AJS-SMEDDS formulation was optimized in terms of drug solubility in the excipients, droplet size, stability, and drug precipitation using a pseudo-ternary diagram. The pharmacokinetic study was performed in rats, and the drug concentration in plasma samples was assayed using the high-performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-MS/MS) method. The optimized formulation for SMEDDS has a composition of castor oil 24.5%, Labrasol 28.6%, Cremphor EL 40.8%, and Transcutol HP 2.7% (co-surfactant). No drug precipitation or phase separation was observed from the optimized formulation after 3 months of storing at 25°C. The droplet size of microemulsion formed by the optimized formulation was 26.08 ± 1.68 nm, and the zeta potential was −2.76 mV. The oral bioavailability of AJS-SMEDDS was increased by 3.4- and 35.9-fold, respectively, compared with the solid dispersion and cyclodextrin inclusion; meanwhile, the C_max of AJS-SMEDDS was about 2- and 40-fold as great as the two controls, respectively. In summary, the present SMEDDS enhanced oral bioavailability of AJS and was a promising strategy to orally deliver the drug.KEY WORDS: bioavailability, HPLC-MS/MS, self-microemulsifying drug delivery system, solubilization, stability     

Flavonoids protect pancreatic beta-cells from cytokines mediated apoptosis through the activation of PI3-kinase pathway

The preventive effects of four phenolic compounds against cytokines-induced β-cell destruction were assessed in this study. Treatment of INS-1 (832/13) cells with pro-inflammatory cytokine mixtures (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)) resulted in an increased apoptosis. While resveratrol or myricetin failed to prevent cell apoptosis, quercetin or naringenin treatment exhibited an about 40% less in cell death induced by cytokines-mediated damage. This protective effect of quercetin or naringenin might be mediated partially via the activation of the downstream pAkt and pBad pathways, an outcome which was abolished by pretreatment with a specific PI3-kinase inhibitor. Cellular protein levels of p-p38 MAPK and inducible NO synthase (iNOS) were enhanced after cytokines addition; however, the presence of quercetin or naringenin could not suppress their expression. While cytokines induced MnSOD, quercetin or naringnin did not further enhance expression of this protective protein. In addition, the loss of mitochondria membrane potential (MMP) after cytokines treatment might be partially corrected with quercetin or naringenin. However, none of the phenolic compounds tested in this study reversed the blunted glucose-stimulated insulin secretion after cytokines treatment. These results suggest that quercetin or naringenin might possibly be able to protect β-cells from cytokines toxicity by enhancing cell survival through PI3-kinase pathway, independent of p-p38 MAPK or iNOS.     

Acetaminophen inhibits cytochrome c redox cycling induced lipid peroxidation

Recent evidence indicates that site-specific crosstalk between O-GlcNAcylation and phosphorylation and the O-GlcNAcylation of kinases play an important role in regulating cell signaling. However, relatively few kinases have been analyzed for O-GlcNAcylation. Here, we identify additional kinases that are substrates for O-GlcNAcylation using an in vitro OGT assay on a functional kinase array. Forty-two kinases were O-GlcNAcylated in vitro, representing 39% of the kinases on the array. In addition, we confirmed the in vivo O-GlcNAcylation of three identified kinases. Our results suggest that O-GlcNAcylation may directly regulate a substantial number of kinases and illustrates the increasingly complex relationship between O-GlcNAcylation and phosphorylation in cellular signaling.     

Peptidomic analyses of mouse astrocytic cell lines and rat primary cultured astrocytes

Astrocytes play an active role in the modulation of synaptic transmission by releasing cell-cell signaling molecules in response to various stimuli that evoke a Ca(2+) increase. We expand on recent studies of astrocyte intracellular and secreted proteins by examining the astrocyte peptidome in mouse astrocytic cell lines and rat primary cultured astrocytes, as well as those peptides secreted from mouse astrocytic cell lines in response to Ca(2+)-dependent stimulations. We identified 57 peptides derived from 24 proteins with LC-MS/MS and CE-MS/MS in the astrocytes. Among the secreted peptides, four peptides derived from elongation factor 1, macrophage migration inhibitory factor, peroxiredoxin-5, and galectin-1 were putatively identified by mass-matching to peptides confirmed to be found in astrocytes. Other peptides in the secretion study were mass-matched to those found in prior peptidomics analyses on mouse brain tissue. Complex peptide profiles were observed after stimulation, suggesting that astrocytes are actively involved in peptide secretion. Twenty-six peptides were observed in multiple stimulation experiments but not in controls and thus appear to be released in a Ca(2+)-dependent manner. These results can be used in future investigations to better understand stimulus-dependent mechanisms of astrocyte peptide secretion.     

Preventive oral supplementation with glutamine and arginine has beneficial effects on the intestinal mucosa and inflammatory cytokines in endotoxemic rats

The objective of this study was to evaluate the effect of oral supplementation with a combination of arginine and glutamine on the intestinal mucosa and inflammatory cytokines of lipopolysaccharide (LPS)-induced adult rats. Fifty Sprague-Dawley rats (average weight of 185 ± 15 g) were randomly divided into five groups: control group A (CA) and control group B (CB), both orally supplemented with 0.9% saline; group Arg, supplemented with 300 mg/kg day(-1) arginine; group Gln, supplemented with 300 mg/kg day(-1) glutamine; group AG, supplemented with 150 mg/kg day(-1) arginine and 150 mg/kg day(-1) glutamine. The experiment lasted for 2 weeks. Food intake and body weight were measured during the experiment. At 10.00 h of day 15, animals were injected with 4 mg/kg LPS (group CB, Arg, Gln, and AG) or sterile saline (group CA) after supplementation. Then at 14.00 h, all animals were killed and blood and tissue collected. The results showed that compared with group CB, arginine concentration tended to be increased (P > 0.05) in group Arg and AG, while there was no significant difference in glutamine concentration among the groups challenged with LPS. Oral supplementation with arginine or/and glutamine mitigated morphology impairment (lower villus height, P < 0.05) in the jejunum and ileum induced by LPS challenge. LPS administration resulted in a significant increase in TNF-α, IL-1β, IL-6 and IL-10 mRNA abundance. Arginine only significantly decreased TNF-α mRNA abundance in the ileum, while glutamine significantly decreased both TNF-α and IL-10 mRNA in the ileum. A combination of arginine and glutamine significantly decreased TNF-α and IL-1β mRNA abundance in both the jejunum and ileum, while they also significantly decreased anti-inflammatory IL-10 in the ileum. These results revealed that an oral supply of combined arginine and glutamine had more favorable effects on the intestinal mucosa and inflammatory cytokines than a supply of arginine or glutamine alone.