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The aim of this study was to explore the function of glycyrrhizic acid (GA) in an anti-psoriatic dermal delivery, whereby GA is originally designed as the matrix agent, with curcumin (Cur) as the active agent and silica as the drug carrier. Formulations with different GA proportions were prepared and named W-GA (without GA), L-GA (13% w/w GA) and H-GA (26% w/w GA). The results showed that GA had no significant effect on the physical characteristics, such as particle size and amorphous state, as exhibited by scanning electron microscopy and x-ray diffractograms, respectively. Compared with W-GA and L-GA, H-GA resulted in 10% less photodegradation of Cur after storage for one month, 0.45 µg more penetrated Cur in the epidermis, 2-fold higher viscosity, fewer signals of imiquimod-induced psoriasiform skin lesions and less histological morphological changes. The findings showed that H-GA significantly inhibited expression of interleukin 17 A in the dermis, and interleukin IL-23 in the epidermis, compared with Cur raw drug powder (RDP), whereas L-GA had no significant effect on the expression. These results indicated that a high GA proportion results in superior anti-psoriatic efficacy. Therefore, Cur-loaded silicas with approximately 26% GA are recommended as the superior formulation for the treatment of psoriasis.

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We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA-seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked-down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin-treated U251/U87 cells. Oridonin treatment led to PCK2 down-regulation. Additionally, PCK2 was up-regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti-tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

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BACKGROUND: Pancreatic cancer (PC) is one of the most well-known malignancies with high mortality, but the underlying mechanism of PC remains unknown. Keratin17 (KRT17) expression has been reported in many malignancies, but its functions in PC are not clear. The aim of our study was to evaluate KRT17 expression and its potential role in PC. METHODS: The online databases GEPIA and THPA were used to identify KRT17 expression in tissues. Quantitative real-time PCR (qRT-PCR) was used to determine KRT17 expression in cell lines. Ki67 and ROS levels were detected by immunofluorescence assay and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. KRT17 downregulation was induced by the small interfering RNA (siRNA) technique. Proliferation function was evaluated by colony formation assay and RTCA. Migration and invasion were evaluated by transwell migration assay. A Western blot assay was used to detect protein levels. RESULTS: KRT17 was overexpressed in PC tissues compared to that in normal tissues. The results showed that Ki67 and ROS levels were decreased in pancreatic cancer cells after transfection with siKRT17. After KRT17 downregulation in PC cell lines, cell viability functions, including proliferation, migration and invasion, and mTOR/S6K1 phosphorylation levels were attenuated. CONCLUSION: KRT17 knockdown significantly inhibited proliferation, migration and invasion in pancreatic cancer cells.

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smartPearls technology is one appropriate method to produce anti-psoriatic curcumin (Cur) topical delivery system. To prevent the sedimentation of loaded silica and release changing over the storage, which are disadvantages of smartPearls production, extra glycyrrhizic acid (GA) was added in classical smartPearls ingredients (active and porous material) to get an improved smartPearls production (Cur-GA-silica). The capacity of Cur-GA-silica to remain the gelation state after mixing with water was superior compared to that of the solid cluster without GA and that of the physical mixture of Cur, GA and silica. The Cur-GA-silica practically contained Cur with 1.68% ± 0.12% and showed significant difference with Cur raw drug powder in kinetic solubilities (4.55 ± 0.78 µg/mL vs 0 in 5 min; 3.26 ± 0.17 µg/mL vs 0 in 4 h) which was traceable to the amorphous state of Cur-GA-silica detected by X-ray diffractometer. With the amorphous Cur, two times as much penetrated Cur in Cur-GA-silica as in Cur raw drug powder was achieved on the imiquimod-induced psoriasis-like mice model. The anti-psoriatic efficacy of Cur-GA-silica was confirmed by Psoriasis Area and Severity Index (PASI) evaluation, histological evaluation and decreased IL-17A in the imiquimod-induced psoriasiform mouse skin analyzed by enzyme-linked immunosorbent assay. In conclusion, with the addition of GA, a stable amorphous curcumin topical vehicle fabricated by smartPearls technology without extra dermal matrix is available and facilitates penetration efficacy and anti-psoriatic capacity in imiquimod-induced psoriasiform mice.

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OBJECTIVE: Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. METHODS: We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. RESULTS: Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. CONCLUSIONS: This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.

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BACKGROUND: Intracerebral hemorrhage (ICH) pathophysiology involves inflammation. Macrophage migration inhibition factor (MIF), a pro-inflammatory cytokine, is related to prognosis of ischemic stroke. The aim of this study was to investigate whether serum MIF levels are associated with severity and outcomes in patients with acute ICH. METHODS: We enrolled a total of 120 consecutive ICH patients and 120 healthy controls and sampled blood on admission and at study entry respectively. Enzyme-linked immunosorbent assay was used to quantify serum MIF levels. RESULTS: Serum MIF levels were higher in patients compared with controls and correlated with hematoma volume, National Institutes of Health Stroke Scale (NIHSS) scores and plasma C-reactive protein levels. After adjusting for other significant outcome predictors, MIF in serum was an independent predictor of 6-month overall survival and unfavorable outcome (modified Rankin Scale score >2). Areas under receiver-operating characteristic curve (ROC) of serum MIF levels, hematoma volume and NIHSS scores were similar for 6-month unfavorable outcome. Moreover, serum MIF levels significantly improved areas under ROC of hematoma volume and NIHSS scores. CONCLUSIONS: MIF in serum might be a potential biomarker for reflecting inflammation, severity and prognosis of ICH patients.

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BACKGROUND: Increased circulating soluble CD40 ligand (sCD40L) levels have been reported to be associated with severity and mortality of severe traumatic brain injury. The current study tested the hypothesis that elevated plasma sCD40L levels are predictive of clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Plasma sCD40L concentrations of 120 aSAH patients and 120 healthy volunteers were measured using enzyme-linked immunosorbent assay. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. RESULTS: Plasma sCD40L levels were significantly elevated in aSAH patients compared with healthy controls; plasma sCD40L levels were highly associated with clinical severity reflected by World Federation of Neurological Surgeons (WFNS) score and Fisher score; sCD40L emerged as an independent predictor of 6-month mortality and unfavorable outcome and 6-month overall survival; although a combined logistic-regression model did not demonstrate the additive benefit of sCD40L to WFNS score and Fisher score, sCD40L possessed similar predictive value to WFNS score and Fisher score based on receiver operating characteristic curves. CONCLUSIONS: Higher plasma sCD40L levels on presentation are associated with clinical severity and have potential to be a good prognostic biomarker of aSAH.

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Increased plasma adrenomedullin levels have been reported in critically ill patients. This study tested the hypothesis that plasma adrenomedullin levels are significantly increased in patients with acute spontaneous aneurysmal subarachnoid hemorrhage, and are predictive of clinical outcomes. Plasma adrenomedullin levels from 120 adult patients with spontaneous aneurysmal subarachnoid hemorrhage and 120 healthy volunteers during the study period were evaluated. Mortality and poor long-term outcome (Glasgow Outcome Scale score of 1-3) at 6 months were recorded. Data showed that circulating plasma adrenomedullin levels significantly increased in patients on admission compared with the volunteers. In patients who died or had poor outcome at 6 months, plasma adrenomedullin levels were significantly higher compared with survivors and patients with good outcome. Plasma adrenomedullin levels on presentation were highly associated with clinical severity assessed using World Federation of Neurological Surgeons score and Fisher score, emerged as the independent risk factor of 6-month mortality and poor outcome, and possessed similar predictive value to World Federation of Neurological Surgeons score and Fisher score based on receiver operating characteristic curves. A combined logistic-regression model did not demonstrate the additive benefit of adrenomedullin to World Federation of Neurological Surgeons score and Fisher score. Thus, higher plasma adrenomedullin levels on presentation are associated with clinical severity and worse outcomes in patients with acute spontaneous aneurysmal subarachnoid hemorrhage.

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BACKGROUND: Phosphorylated axonal neurofilament subunit H (pNF-H) is a biomarker of axonal injury. We investigated whether plasma pNF-H concentrations were associated with 6-month clinical outcomes and early neurological deterioration (END) of patients with acute intracerebral hemorrhage. METHODS: Plasma pNF-H concentrations of 112 patients and 112 healthy individuals were quantified by ELISA. Unfavorable outcome was defined as modified Rankin Scale score >2. Associations of plasma pNF-H concentrations with END, 6-month mortality and unfavorable outcome were evaluated. RESULTS: Plasma pNF-H concentrations were increased in patients than in healthy individuals [700.2 (430.8) pg/ml vs. 25.5 (32.4) pg/ml, P<0.001]. A logistic regression analysis selected plasma pNF-H concentration as an independent predictor for 6-month mortality [OR: 1.287, 95% CI: 1.140-1.524, P<0.001], 6-month unfavorable outcome (OR 1.265, 95% CI 1.121-1.517, P<0.001) and END (OR 1.246, 95% CI 1.109-1.498, P<0.001). A receiver operating characteristic curve analysis showed that plasma pNF-H concentration predicted 6-month clinical outcomes and END with high area under curves (all P<0.001). The predictive value of pNF-H was similar to that of the National Institutes of Health Stroke Scale score (all P>0.05). In a combined logistic-regression model, pNF-H did not improve the predictive value of National Institutes of Health Stroke Scale score (all P>0.05). CONCLUSIONS: Increased plasma pNF-H concentration was highly associated with 6-month clinical outcomes and END of patients with intracerebral hemorrhage.

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