Artocarpin attenuates ultraviolet B-induced skin damage in hairless mice by antioxidant and anti-inflammatory effect

Artocarpin, a prenylated flavonoid isolated from an agricultural plant Artocarpus communis, has been documented to possess anti-inflammation and anticancer activities. As oxidative stress and inflammation promote the development of ultraviolet B (UVB) irradiation-induced photodamage, the aim of the present study was to evaluate the photoprotective effect of artocarpin on UVB-induced skin damage in hairless mice. Artocarpin at a topical dose of 0.05% and 0.1% showed a significant photoprotective effect by decreasing histopathological changes, such as desquamation, epidermal thicken and sunburn cell formation, but 0.1% of artocarpin administration did not show better effect. Regarding the antioxidant activities, artocarpin exhibited a significant effect (P < 0.05) by decreasing levels of reactive species oxygen and lipid peroxidation. In addition, artocarpin can significantdecrease the level of tumor necrosis factor-α and interleukin-1β for downregulating the inflammation protein, including the synthesis of cytosolic phospholipase A2 and cyclooxygenase-2 (P < 0.05). In conclusion, these data suggest that artocarpin can prevent skin damage from UVB irradiation-induced photodamage in hairless mice and this is likely mediated through its antioxidant and anti-inflammation mechanisms. Therefore, we suggested that artocarpin could be a useful photoprotective agent in medicine and/or cosmetics.     

Inhibition of UVB-induced skin phototoxicity by a grape seed extract as modulator of nitrosative stress,ERK/NF-kB signaling pathway and apoptosis,in SKH-1 mice

Molecular mechanisms concerning the modulation of nitrosative stress, signal transduction and proliferation/apoptosis by a grape seed extract, Burgund Mare variety (BM), in SKH-1 mice exposed to UVB, were investigated. The animals were irradiated with single and multiple doses of UVB in 10 consecutive days. In each experiment were used five groups of animals: control, vehicle, UVB irradiated, vehicle + UVB, BM + UVB. The extract was applied topically, 30 min before each UVB exposure, in a dose of 4 mg total polyphenols/cm². BM remarkably inhibited UVB-induced activation of inducible nitric oxide synthase (iNOS) and therefore generation of nitric oxide (NO) and nitrotyrosine, in a UVB single dose regimen. BM also suppressed NF-kB activation by UVB but did not affect the activity of total ERK 1/2. In multiple UVB irradiations, BM increased NO formation and total ERK 1/2 activity and reduced iNOS activity and nitrotyrosine levels, inhibited cell proliferation, diminished p53 and caspase-3 immunoreactivities and increased the percentage of Bcl-2 positive cells. We concluded that BM modulates the apoptotic response of SKH-1 mice skin in UVB irradiation by the inhibition of p53, caspase-3, Bax/Bcl-2 and proliferating cell nuclear antigen expressions, as well as by reducing the activation of iNOS and NF-kB.     

Suppressive effect of β,β-dimethylacryloyl alkannin on activated dendritic cells in psoriasis by the TLR7/8 pathway

β,β-dimethylacryloyl alkannin (DMA) is a key component of Lithospermum and possesses good efficacy for treating psoriasis. DMA inhibits activated dendritic cells (DCs), but the mechanism is unknown. Therefore, this study aimed to explore the modulation of the TLR7/8 pathway by DMA in psoriasis-activated DCs. Models of psoriasis-like skin lesions were established using BALB/c mice; 8 mice were treated with DMA (2.5 mg/kg). Bone marrow cells were isolated and induced into DCs using R848, a TLR7/8 agonist. Splenic CD11c + cells were detected by flow cytometry. Skin CD11c + cells were detected by immunofluorescence. TLR7, TLR8, MYD88, and IRAKM proteins were detected by Western blot. The effects of DMA on surface molecules of DCs were observed by flow cytometry. mRNA expression of inflammatory factors was detected by qRT-PCR. Secreted cytokines were detected by cytometric bead array. Compared with the model group, psoriasis-like skin lesions were alleviated by DMA, the splenic CD11c + cells were significantly decreased (P < 0.01), and CD11c + cell numbers in skin lesions were decreased (P < 0.01). Expression levels of TLR7, MYD88, and IRAKM were significantly decreased (P < 0.05). R848-stimulated DCs showed increased expression of I-A/I-E, CD80, and CD86 (P < 0.01), increased IL-23 and IL-1β mRNA and secretion (P < 0.05), and increased TLR7, TLR8, MYD88, and IRAKM expression (P < 0.01); DMA inhibited all of these effects of the TLR7/8 pathway activation by R848 (P < 0.05). In conclusion, DMA could inhibit psoriasis-activated DCs via the TLR7/8 pathway.     

Free radicals and antioxidant status in rat liver after dietary exposure of environmental mercury

Potential health effect of dietary exposure to environmental mercury was examined in this study. Dietary exposure significantly increased content of reduced glutathione (GSH) and activity of glutathione peroxidase (GSH-Px) in rat liver at 7 or 20 days (P < 0.05; P < 0.01), but parameters droped to normal levels after 90 days of exposure. The early increases of the two antioxidants were partly associated with the co-accumulated selenium. However, activity of superoxide dismutase (SOD) was observed significantly decreased after 30 and 90 days of exposure (P < 0.05, P < 0.05). Changes of antioxidants were paralleled by the induction and aggravation of free radicals in rat liver at 30 and 90 days (P < 0.01, P < 0.01), increased nitric oxide (NO) content at 90 days (P < 0.01). The excess availability of free radicals and the decreased levels of antioxidants resulted in a significant increase of malonyldialdehyde (MDA) after 90 days of exposure, indicating the aggravation of hepatic oxidative status. A number of biomarkers were required to monitor and minimize the health risk for the local population.     

Regulation of arginase/nitric oxide synthesis axis via cytokine balance contributes to the healing action of malabaricone B against indomethacin-induced gastric ulceration in mice

The role of the arginine-metabolism in the healing action of the Myristica malabarica phenol malabaricone B (mal B) and omeprazole against indomethacin-induced stomach ulceration in mouse was investigated. Indomethacin (18 mg kg^− 1) was found to induce maximum stomach ulceration in Swiss albino mice on the 3rd day of its administration, which was associated with reduced arginase activity (30.8%, P < 0.01), eNOS expression, along with increased iNOS expression, total NOS activity (5.55 folds, P < 0.001), NO generation (2.19 folds, P < 0.001), and ratio of pro-/anti-inflammatory cytokines. Besides providing comparable healing as omeprazole (3 mg kg^− 1 × 3 days), mal B (10 mg kg^− 1 × 3 days, p. o.) shifted the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity (51.6%, P < 0.001), eNOS expression, and reduced iNOS expression, total NOS activity (~ 75%, P < 0.001), and NO level (50.6%, P < 0.01). These could be attributed to a favourable anti/pro inflammatory cytokines ratio, generated by mal B. The healing by omeprazole was however, not significantly associated with those parameters.     

Pig and guinea pig skin as surrogates for human in vitro penetration studies: A quantitative review

Both human and animal skin in vitro models are used to predict percutaneous penetration in humans. The objective of this review is a quantitative comparison of permeability and lag time measurements between human and animal skin, including an evaluation of the intra and inter species variability. We limit our focus to domestic pig and rodent guinea pig skin as surrogates for human skin, and consider only studies in which both animal and human penetration of a given chemical were measured jointly in the same lab. When the in vitro permeability of pig and human skin were compared, the Pearson product moment correlation coefficient (r) was 0.88 (P < 0.0001), with an intra species average coefficient of variation of skin permeability of 21% for pig and 35% for human, and an inter species average coefficient of variation of 37% for the set of studied compounds (n = 41). The lag times of pig skin and human skin did not correlate (r = 0.35, P = 0.26). When the in vitro permeability of guinea pig and human skin were compared, r = 0.96 (P < 0.0001), with an average intra species coefficient of variation of 19% for guinea pig and 24% for human, and an inter species coefficient of variation of permeability of 41% for the set of studied compounds (n = 15). Lag times of guinea pig and human skin correlated (r = 0.90, P < 0.0001, n = 12). When permeability data was not reported a factor of difference (FOD) of animal to human skin was calculated for pig skin (n = 50) and guinea pig skin (n = 25). For pig skin, 80% of measurements fell within the range 0.3 < FOD < 3. For guinea pig skin, 65% fell within that range. Both pig and guinea pig are good models for human skin permeability and have less variability than the human skin model. The skin model of choice will depend on the final purpose of the study and the compound under investigation.     

Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice

The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively. Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0.001), body weight (p < 0.01), circulating insulin and LDL-cholesterol (p < 0.001) and improved insulin sensitivity (p < 0.001) as well as oral and intraperitoneal (p < 0.001) glucose tolerance. Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls. In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle. Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0.001) elevated pancreatic glucagon content. Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0.001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1. Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0.05), body weight (p < 0.05 to p < 0.01), circulating glucose (p < 0.05 to p < 0.01) and insulin (p < 0.05 to p < 0.001) and improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Notably, these beneficial effects were still evident 18 days following cessation of treatment. These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes.     

Effects of topical pimecrolimus 1% on high-dose ultraviolet B-irradiated epidermal Langerhans cells

Some studies reported no changes in the number of epidermal Langerhans cells (LC) that were observed in mice treated with pimecrolimus, and low-dose stimulated solar radiation (once)-induced changers in LC are minimally affected by pimecrolimus. This study is to investigate the effects of topical pimecrolimus 1% on high-dose ultraviolet B (UVB)-irradiated epidermal LC. Forty human foreskin tissues were randomly divided into 4 groups of 10 tissues each: Group A, control; Group B, pimecrolimus 1% (once)-only; Group C, 180 mJ/cm² UVB (once)-only; Group D, UVB + pimecrolimus. Each tissue was cut into 4 pieces corresponding to 4 time points. All the tissues were cultured at 37 °C. After being treated, the tissues were collected respectively and processed for immunohistochemical staining and immunofluorescence staining. For UVB-only group, epidermal CD1a⁺ LC number at 18 h decreased from 39.6 ± 8.30 to 22.3 ± 2.26/5 high magnification, compared to CD1a⁺ LC number at 0 h (P < 0.01). The CD1a⁺ LC number of UVB-only group was significantly less than other groups at 18 h, 24 h and 48 h (P < 0.05, respectively). Similar results were obtained with immunofluorescence staining for CD 1a and immunohistochemical staining for Langerin. The numbers of epidermal HLA-DR⁺ LC had no significant differences among all groups at different time points. Our study found a single 180 mJ/cm² UVB irradiation significantly reduced epidermal LC numbers at 18 h, 24 h and 48 h, however, topical pimecrolimus could reverse these changes. UVB plus pimecrolimus treatment did not affect human LC maturation.     

The effects of sulfur mustard exposure and freezing on transdermal penetration of tritiated water through ex vivo pig skin

The percutaneous absorption of tritiated water (³H₂O) through sulfur mustard (SM) exposed abdominal pig skin was measured using in vitro Franz-type static diffusion cells. The barrier function to water permeation following exposure to liquid SM for 8 min and excision 3 h later did not change significantly. A small, but statistically significant difference (P < 0.05) in steady state penetration (Jss), permeability coefficient (Kp) and lag time (t_L) of ³H₂O was observed between fresh skin and skin stored frozen (?20 °C) for up to two weeks. Steady-state penetration and Kp values were significantly higher (P < 0.05) in skin stored frozen compared with fresh skin. Fresh naïve skin had an average Kp of 1.65 × 10^?3 cm h^?1, whereas frozen naïve skin was 2.04 × 10^?3 cm h^?1. Fresh SM exposed skin had a mean Kp of 1.72 × 10^?3 cm h^?1, whereas frozen SM exposed skin was 2.31 × 10^?3 cm h^?1. Lag times were also shorter (P < 0.05) in skin that had been stored frozen. Frozen, SM-exposed porcine abdominal skin may be used for in vitro penetration studies, but effects of treatment and storage on the barrier layer should be taken into account.     

Efficacy of voriconazole in a murine model of invasive paecilomycosis

We studied the efficacy of voriconazole (VRC) and amphotericin B (AMB) in an immunosuppressed murine model of disseminated infection by two strains of Paecilomyces lilacinus. Mice were treated with VRC 60 mg/kg/day orally or AMB 3 mg/kg/day intraperitoneally, beginning 1 day after infection and continuing for 9 days. To avoid rapid clearance of VRC, animals receiving VRC and the control group were given grapefruit juice instead of water. VRC significantly prolonged survival with respect to the group treated with AMB and the control group for both strains (P = 0.005 and P < 0.0001, respectively, for strain FMR 5522; and P = 0.0002 and P < 0.0001, respectively, for strain FMR 8252). VRC reduced the fungal load in the spleen, kidneys and liver of infected mice for both strains tested. Survival of mice challenged with strain FMR 8252 treated with AMB did not differ from that of the control group (P = 0.223), being worse than that of the mice treated with VRC (P = 0.0002). AMB was not able to reduce the tissue burden in any organ with respect to the control group for both strains studied.     

Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes

Increased TNFα-mediated JNK signaling in the perivascular adipose tissue (PVAT) may contribute to the pathogenesis of vascular complications in T1DM by reducing adiponectin (Ad) synthesis and therefore impairing Ad-mediated activity in the contiguous blood vessel system.We evaluated whether in vivo treatment with the TNFα blocking antibody infliximab normalized expression of Ad and Ad receptors in various fat depots, and whether this effect correlated with improved endothelial activity and vasodilator function in streptozotocin (STZ)-induced diabetic mice. STZ mice were studied at 1 and 2 weeks after diabetes onset, and compared to age-matched infliximab-treated diabetic (I-STZ) and control animals (CTRL) (n = 10 each group). In STZ mice, activation of pro-inflammatory JNK signaling was faster in PVAT (P < 0.01) than in visceral (VAT), epididymal (EAT) and subcutaneous (SAT) adipose depots, and associated with decreased Ad synthesis and dysregulated AdipoR1/R2 levels. In parallel, activation of JNK in aortic endothelial cells and mesenteric arteries was associated with decreased expression/phosphorylation of eNOS and impaired ACh-mediated vasodilation (P < 0.05 vs. CTRL). Treatment with infliximab abrogated JNK activation, ameliorated Ad protein expression, and normalized expression of both AdipoR1 and AdipoR2 in PVAT, concomitantly improving eNOS expression and vessel relaxation in mesenteric arteries from I-STZ mice (P < 0.01 vs. STZ).These observations underline the early susceptibility of PVAT to activation of pro-inflammatory JNK signaling, and highlight its potential importance in early vascular changes of T1DM. Further elucidation of the role of PVAT in cardiovascular complications may allow for the design of novel therapeutic strategies directly addressing PVAT pathophysiology.     

Consumption of fumonisin B1 for 9 days induces stress proteins along the gastrointestinal tract of pigs

Fumonisin B₁ (FB1) is a mycotoxin which alters intestinal epithelial cell physiology and barrier properties, and accumulates in the colon. Data on effects of FB1 on stress proteins in the gastrointestinal tract (GIT) are lacking. Therefore, we hypothesized that repeated consumption of FB1 alters GIT tissue levels of stress proteins. This was tested using 36 weaned pigs fed a FB1 solution (n = 18) or the vehicle (control; n = 18) for 9 days. The pigs were then slaughtered, the organs were weighed and GIT tissues were collected for assessing GIT integrity, and for analysing stress proteins by Western blotting and densitometry (n = 7 in each group). FB1 had little effects on growth rate but the liver was heavier (P < 0.01) in FB1-fed pigs. αB crystallin and COX-1 concentrations were eight-fold and 12-fold higher in the colon of FB1-fed pigs than in the controls (P < 0.0001). Concentrations of COX-1 and nNOS in the stomach, HSP 70 in the jejunum and HO-2 in the colon were also higher in FB1-fed pigs (P < 0.05 to P < 0.001). In conclusion, the FB1 extract drastically enhanced colonic levels of αB crystallin and COX-1, with milder increases in other stress proteins along the GIT of pigs. The data suggest that the colon is an important target for FB1-induced stress responses.     

Effects of N-(morpholinomethyl)- p-isopropoxyphenylsuccinimide on the protective action of different classical antiepileptic drugs against maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effects of N-(morpholinomethyl)-p-isopropoxy-phenylsuccinimide (MMIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) against maximal electroshock (MES)-induced seizures in mice.MethodsTonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of AEDs were measured to determine the characteristics of interaction between MMIPPS and classical AEDs in the mouse MES model.ResultsMMIPPS administered intraperitoneally (ip) at 100 mg/kg significantly elevated the threshold for electroconvulsions in mice (p < 0.01). MMIPPS at doses of 25 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, MMIPPS (50 mg/kg) significantly enhanced the anticonvulsant activity of PB and VPA(p < 0.05), but not that of CBZ or PHT, in the MES test in mice. Pharmacokinetic studies revealed that MMIPPS (50 mg/kg) did not alter total brain concentrations of PB, but significantly elevated total brain concentrations of VPA in mice (p < 0.05).ConclusionsThe enhanced anticonvulsant action of PB byMMIPPS in themouseMESmodel and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPAconcentration seems to be responsible for the enhanced anticonvulsant action of VPAby MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint.     

Formulation and clinical evaluation of the standardized Litchi chinensis extract for skin hyperpigmentation and aging treatments

IntroductionThe standardized litchi extract had been revealed on phytochemical actives, in vitro and cellular activities against aging and darkening of skin. However, a formulation containing the extract has never been developed as per clinical evaluated.Materials and methodsThe litchi serum was developed, safety and efficacy were clinically evaluated in human volunteers. The stable and none irritated 0.05 and 0.1% litchi serums were randomized-single blind placebo control clinical applied on the inner forearm of 29 volunteers for a consecutive 112 days and monitored by Mexameter® MX18, Cutometer® MPA 580 and Visioscan® VC 98.ResultsSkin lightening efficacy of the 0.1% and 0.05% litchi serum was significantly (P < 0.001 and P < 0.05) higher than the placebo. Skin elasticity and wrinkle reduction was significantly (P < 0.05 and P < 0.005) achieved by the 0.1% litchi serum. The efficacy of litchi serums was confirmed by a split-face, randomized, single-blind controlled that the 0.1% litchi serum was significantly (P < 0.05) better than the 0.05% one of all examined parameters.ConclusionSafety and efficacy of litchi extract are clinically confirmed for hyperpigmentation and aging of skin treatments.     

Reversing the polarization of tumor-associated macrophages inhibits tumor metastasis

ObjectiveThe M2 phenotype is dominant in tumor associated macrophages (TAM), and plays a key role in promoting tumor growth, invasion and metastasis. Converting TAM polarization from M2 to M1 may contribute to eliciting anti-tumor-specific immune responses and inhibiting tumor metastasis. In this study, the effect of reversing the polarization of TAM on tumor metastasis was investigated.MethodsPeritoneal macrophages were obtained from BABL/c mice, and M2 polarization was induced by IL-4. In an in vivo experiment, BABL/c mice were transplanted with 4 T1 tumor cells. In vitro and in vivo experimental studies, M2 macrophage polarization was reversed with CpG-DNA or CpG-DNA combined with anti-IL-10R Ab. CD68, MHCII and FRβ molecular expression in macrophages were examined with immunofluorescence staining. The mRNA expression of IL-2, IL-6, IL-13, VEGF and MMP-9 were detected with RT-PCR. VEGF and MMP-9 protein expression of tumors in situ was measured by western blot assay. Lung-metastasis of the tumor was observed and assessed by micro-CT.ResultsCpG-DNA and CpG-DNA combined with anti-IL-10R Ab could promote MHCII, IL-2, IL-6 and IL-13 molecular expression, and suppress the expression of FRβ, MMP-9 and VEGF, in both freshly isolated peritoneal macrophages and M2 macrophages. In the CpG-DNA combined with anti-IL-10R Ab injecting group, the percentage of CD68⁺ MHCII⁺ cells were significantly higher than that of CD68⁺ FRβ⁺ cells (P < 0.05). This was distinct from the result of the control group, which CD68⁺ FRβ⁺ was higher than CD68⁺ MHCII⁺ cells (P < 0.01). Furthermore, VEGF-A and MMP-9 level in primary tumor tissues in the experimental group was significantly lower (P < 0.01), compared to the control group. Moreover, the number of detectable lung-metastasis foci was significantly lower in the experimental group than in the control group (P < 0.05).ConclusionReversing the polarization of TAM from M2 to M1 phenotype can inhibit tumor metastasis.     

Zearalenone inhibits testosterone biosynthesis in mouse Leydig cells via the crosstalk of estrogen receptor signaling and orphan nuclear receptor Nur77 expression

Zearalenone (ZEA) directly inhibits testosterone biosynthesis in Leydig cells, although the mechanisms involved remains unclear. Various experiments were performed to elucidate the molecular pathway of ZEA-mediated androgen inhibition. Leydig cells were isolated from 6 week-old male ICR mice and subjected to ZEA pre-treatment. The levels of testosterone and a series of influncing factors were measured. The results showed that ZEA caused a concentration- and time-dependent inhibition of testosterone stimulated both by hCG and cAMP (P < 0.05). Exposure to ZEA did not affect the LHR binding activity nor the protein expression (P > 0.05). However, ZEA exposure significantly elevated the cellular cAMP levels (P < 0.05) in low concentrations (5 μg/ml) or for long time periods (24 h), significantly reduce the mitochondrial membrane potential (P < 0.05). The expression of P450scc, 17β-HSD, and P450c17 at the mRNA level were significantly decreased (P < 0.05). The steroidogenic acute regulatory (StAR) and 3β-HSD expression was significantly increased (P < 0.05). Furthermore, the ERα protein expression was not affected by ZEA, but Nur77 expression was significantly inhibited (P < 0.05). These observations imply that ZEA activity interferes with testosterone biosynthesis in mouse Leydig cells via the crosstalk of estrogen receptor signaling and Nur77 expression.     

The application of 2-NBDG as a fluorescent tracer for assessing hepatic glucose production in mice during hyperinsulinemic euglycemic clamp

Methods of performing insulin clamps vary between laboratories. Here we present a protocol of insulin clamping in conscious mice, with the significant advantage of avoiding multiple surgical catheterizations and non-physiologic metabolism during the induction of anesthesia. Using this technique we also established a new method for measuring hepatic glucose production (HGP) using a fluorescent d-glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose (2-NBDG). To prove the reliability and feasibility of this method, whole-body insulin sensitivity was compared between conscious normal ICR mice and diabetic KK^Ay mice using the insulin clamp. Basal and clamp HGP was compared between normal C57 mice and diabetic db/db mice by using the modified clamp with 2-NBDG as a tracer. The glucose infusion rate (GIR), an index of insulin sensitivity, was significantly lower in KK^Ay mice than normal ICR mice (6.2±1.3 mg/kg/min vs. 31.3±2.9 mg/kg/min, P<0.001). The db/db mice also showed higher basal hepatic glucose production (25.8±2.2 mg/kg/min vs. 16.7±2.5 mg/kg/min, P<0.05), higher clamp HGP after insulin suppression (7.3±1.0 mg/kg/min vs. 0 mg/kg/min, P<0.001), and lower GIR (71.6±2.8 mg/kg/min vs. 15.2±1.6 mg/kg/min, P<0.001) than that obtained with normal C57 mice. In conclusion, this is the first report of the application of 2-NBDG, rather than isotopic tracers, for the determination of HGP in vivo.     

Antidiabetic effects of cinnamon oil in diabetic KK-Ay mice

The hypoglycemic effect of cinnamon oil (CO) in a type 2 diabetic animal model (KK-A^y mice) was studied. The main component of CO was cinnamaldehyde, and other nineteen components were also determined. CO was administrated at doses of 25, 50 and 100 mg/kg for 35 days. It was found that fasting blood glucose concentration was significantly decreased (P < 0.05) with the 100 mg/kg group (P < 0.01) the most efficient compared with the diabetic control group. In addition, there was significant decrease in plasma C-peptide, serum triglyceride, total cholesterol and blood urea nitrogen levels while serum high density lipoprotein (HDL)-cholesterol levels were significantly increased after 35 days. Meanwhile, glucose tolerance was improved, and the immunoreactive of pancreatic islets β-cells was promoted. These results suggest that CO had a regulative role in blood glucose level and lipids, and improved the function of pancreatic islets. Cinnamon oil may be useful in the treatment of type 2 diabetes mellitus.     

D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D₁-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P < 0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D₁-like receptor antagonist (P < 0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P < 0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P < 0.05). These results suggest a role for D₁-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.     

Association of CD40 − 1C/T polymorphism with cerebral infarction susceptibility and its effect on sCD40L in Chinese population

This study aims to determine whether functional polymorphism of CD40 is associated with the cerebral infarction (CI) susceptibility, and to investigate the effect of CD40 gene polymorphism on CD40 mRNA expression in PBMCs and plasma sCD40L concentration. A case–control study was performed in 402 CI patients and 693 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expressions of CD40 mRNA and plasma sCD40L concentration were determined. The distribution of TT genotype and the frequency of T allele in CI patients were significantly higher than those in the controls (P < 0.05). The frequency of T allele was also significantly higher in the male subjects and the elder subjects (P < 0.05) when stratified analysis was carried out. The PBMCs from CI patients showed significantly higher CD40 mRNA expression than controls (P < 0.01), the CD40 mRNA expression from TT genotype was higher than other genotypes (P < 0.05). TT genotype subjects also showed the highest plasma sCD40L concentration in the male CI patients (P < 0.01). CD40 − 1C/T polymorphism may interfere CI susceptibility, and the T allele may be associated with increased risk of CI. The CD40 − 1C/T polymorphism is also a regulator of CD40 expression and plasma sCD40L concentration.